Note: Descriptions are shown in the official language in which they were submitted.
-- 1 --
I
1 337768
PIPERAZINE DERIVATIVES
BACKGROUND OF THE lNv~NlION
Field of the Invention
The present invention relates to a novel piperazine
derivative.
Description of prior art
Liver is an organ showing various functions such as
10 detoxication, carbohydrate metabolism, lipid metabolism,
protein metabolism, production and secretion of bile,
production of blood coagulation factors, control of pro-
duction of hormones, and storage of various materials
employed for constituting a living body such as fat, gly-
15 cogen, protein and vitamine. These functions of livermay suffer from acute or chronic damages by action of
virus, medicaments, toxic material, alcohol, malnutri-
tion, damage of liver circulation system or bile throm-
bus. Such damages causes various diseases such as virus
20 hepatitis, hepatitis caused by toxicity of medicaments,
alcoholic hepatitis, congestive hepatitis, cholangiolitic
hepatitis, fatty liver an jaundice. Such diseases may
finally cause liver cirrhosis.
Accordingly, studies have been heretofore made for
25 the purpose of finding medicaments for treatment or pre-
vention of liver disease. Based on these studies, a
number of therapeutic agents for liver disease have been
developed and employed in practice. Representative
examples of the known therapeutic agents for liver
- 2 - l 337768
disease include Malotilate (diisopropyl 1,3-dithiol-2-
ylidene malonate), Catergen ((2R,3S)-2-(3,4-dihydroxy-
phenyl)-3,4-dihydro-2H-1-benzopyran-3,5,7-triol), and
Glycyrrhizin (20~-carboxy-11-oxo-30-norolean-12-en-3~-
5 yl-2-0-~-D-glucopyranuronosyl-a-D-glucopyranosiduronic
acid).
The present inventors have made study on piperazine
derivatives and have discovered that speicific piperazine
derivatives and their pharmaceutically acceptable salts
10 are effective for prevention and/or treatment of liver
disease.
There are known a great number of piperazine deriva-
tives. However, there is known no pharmacogical effect
of piperazine derivative as therapeutic agent for liver
15 disease, so long as compounds analogous to the specific
piperazine derivatives found by the present inventors.
For instance, 4-(2-phenylalkyl)-1-piperazine-carbodithio
acid and its alkyl ester is disclosed in Acta Pharm.
Suecica, 7(1), 7-22 (1970). However, no pharmacological
20 effect for prevention or treatment of liver disease is
suggested. Further, 4-(6,7-dihydoxycumarin-8-yl)methyl-
1-piperazine-ethanol is disclosed in Zh. Obshch. Khim.
33(3), 793-7 (1966); 4-{2-(3,4-dihydroxyphenyl)-2-oxo}-
ethyl-1-piperazine-ethanol is disclosed in Latv.
25 PSR Zinat. Akad. Vestis, kim. Ser., (5), 593-6 (1968);
and 4-{2-(3,4-dihydroxyphenyl)-2-oxo~ethyl-1-methyl-
pyperazine is disclosed in Arzneim.-Forsch., 19(10),
1698-1702 (1969). Nevertheless, there is neither dis-
closure nor suggestion to indicate pharacological effect
30 of the disclosed piperazine derivatives with respect to
prevention or treatement of liver disease.
- 3 - l 337768
Canadian patent application no. 589,290 filed January
26, 1989 discloses and claims a novel therapeutic agent for
liver disease containing as an active agent a piperazine
derivative having the formula
(I):
S,
A - B - N N - C - S - R --- (I)
~CH
wherein
A represents a phenyl, p-benzoquinonyl or cumarinyl
group which may have at least one substituent selected
from the group consisting of halogen, alkyl, fluoroalkyl,
formyl, alkoxycarbonyl, acyl, hydroxy, alkoxy, acyloxy,
glycosyloxy, amino, alkylamino, mercapto, alkylthio and
nitro;
B represents a straight chain alkylene group containing 1-4 carbon
atoms which may have at least one substituent selected from the group
consisting of alkyl, aryl, aralkyl, hydroxy and oxo;
R represents an atom or a group selected from the group consisting of
hydrogen, alkali metal, alkaline earth metal, alkyl, cycloalkyl, aralkyl and
aryl; and
n is 2 or 3,
or its pharmaceutically acceptable salt.
1 337768
- _ - 4 -
The above-identified piperazine derivative having
the formula (I) and its pharmaceutically acceptable salt
show favorable action in in-vivo tests for treatment
acute liver disease caused by carbon tetrachloride for
5 inhibition or suppresion of deviation of values of GOT
(glutamic-oxaloacetic transaminase) and GPT (glutamic-
pyruvic transaminase).
Accordingly, the piperazine derivative of the for-
mula (I) and its pharmaceutically acceptable salt accord-
10 ing to the invention are well effective for prevention ortreatment (including tratment for suppresion of disease)
of liver disease.
The piperidine derivative of the formula (I) and its
pharmaceutically acceptable salt further shows inhibitory
15 effect on lipid peroxidation as well as an action for
trapping an active oxygen. It is known that increase of
the lipid peroxide is closely related to diseases of
various organs in a living body. Further, it is known
that increase of the lipid peroxide is also observed when
20 a living body gets old, is exposed to radioactive rays,
or takes medicaments. Therefore, it is considered that
the increase of lipid peroxide is related to aging and
cancer. For this reason, a substance having inhibitory
effect on lipid peroxidation is active not only as a
25 therapeutic agent for lever disease but also as a thera-
peutic agent for treating inflammation, rheumatism,
disease of digestinve tract, cataract, arteriosclerosis,
cerebral infarction, or autoimmune disease.
SUMMARY OF 1NY~;N1~ION
The present invention provides a novel piperazine
derivative having the formula (II):
_ ~ 5 ~ l 337768
Al _ B - N N - C - S - R --- (II)
~CH2~J
wherein
Al represents a phenyl group which has at least one
substituent selected from the group consisting of halo-
gen, alkyl, fluoroalkyl, formyl, alkoxycarbonyl, acyl,
hydroxy, alkoxy, acyloxy, glycosyloxy, amino, alkylamino,
mercapto, alkylthio and nitro, or a p-benzoquinonyl or
10 cumarinyl group which may have at least one substituent
selected from the above group;
B represents a single bond or a straight chain
alkylene group containing 1-4 carbon atoms which may have
at least one substituent selected from the group consist-
15 ing of alkyl, aryl, aralkyl, hydroxy and oxo;
R represents an atom or a group selected from thegroup consisting of hydrogen, alkali metal, alkaline
earth metal, alkyl, cycloalkyl, aralkyl and aryl; and
n is 2 or 3.
DETAILED DESCRIPTION
In the above-mentioned formula (I), A represents one
of phenyl group, p-benzoquinonyl group and cumarinyl
group. These groups may have one or more substituents
such as halogen (e.g., chlorine, bromine or fluorine),
25 alkyl having 1-6 carbon atoms (e.g., methyl, ethyl, pro-
pyl or butyl), fluoroalkyl having 1-6 carbon atoms (e.g.,
trifluoromethyl), formyl, alkoxycarbonyl having 2-7
carbon atoms (e.g., methoxycarbonyl or ethoxycarbonyl),
acyl having 2-7 carbon atoms (e.g., acetyl or propionyl),
30 hydroxy, alkoxy having 1-6 carbon atoms (e.g., methoxy,
ethoxy or propoxy), acyloxy having 2-7 carbon atoms
(e.g., acetoxy or propionyloxy), glycosyloxy (e.g.,
1 33~7~
glycofuranosyloxy, glycopyranosyloxy or glycoseptanosyl-
oxy), amino, alkylamino having 1-6 carbon atoms (e.g.,
monoalkylamino such as monomethylamino or monoethylamino
or dialkylamino such as dimethylamino or diethylamino),
5 mercapto, alkylthio having 1-6 carbon atoms (e.g.,
methylthio, ethylthio or propylthio), and nitro.
The phenyl, p-benzoquinonyl or cumarinyl group may
have one to five substituents on their rings. In the
case that the group has two or more substituents, these
10 substituents may be the same as or different from each
other. In the case that a substituent is attached to a
phenyl group, the substituent is preferably attached to
the ortho-position with respect to the position to which
the bonding or group of "B" is combined. In the case
15 that two hydroxy groups are attached to a phenyl group at
adjoining positions, these hydroxy may be combined via
methylene to form -0-CH2-0- bonding.
In the above-mentioned formula (II), A represents a
phenyl which necessarily has one or more substituents
20 such as halogen (e.g., chlorine, bromine or fluorine),
alkyl having 1-6 carbon atoms (e.g., methyl, ethyl,
propyl or butyl), fluoroalkyl having 1-6 carbon atoms
(e.g., trifluromethyl), formyl, alkoxycarbonyl having 2-7
carbon atoms (e.g., methoxycarbonyl or ethoxycarbonyl),
25 acyl having 2-7 carbon atoms (e.g., acetyl or propionyl),
hydroxy, alkoxy having 1-6 carbon atoms (e.g., methoxy,
ethoxy or propoxy), acyloxy having 2-7 carbon atoms
(e.g., acetoxy or propionyloxy), glycosyloxy (e.g., gly-
cofuranosyloxy, glycopyranosyloxy (e.g., a-D-glucopyrano-
30 syloxy, a-D-galactopyranosyloxl or ~-arabinopyranosyloxy)
or glycoseptanosyloxy), amino, alkylamino having 1-6 car-
bon atoms (e.g., monoalkylamino such as monomethylamino
or monoethylamino or dialkylamino such as dimethylamino
or diethylamino), mercapto, alkylthio having 1-6 carbon
_ 7 - -l 3 3 7 7 6 8
atoms (e.g., methylthio, ethylthio or propylthio), and
nitro.
The phenyl group for "A " in the formula (II) should
have one to five substituents selected from the above
5 listed atoms and groups.
The p-benzoquinonyl or cumarinyl group for "A1" in
the formula (II) may have no substituent or may have one
or more substituents selected from the above listed atoms
and groups.
In the case that the phenyl, p-benzoquinonyl or
cumarinyl group has two or more substituents, these sub-
stituents may be the same as or different from each
other. In the case that a substituent is attached to a
phenyl group, the substituent is preferably attached to
15 the ortho-position with respect to the position to which
the bonding or group of "B" is combined. In the case
that two hydroxy groups are attached to a phenyl group at
adjoining positions, these hydroxy may be combined via
methylene to form -0-CH2-0- bonding.
In the formulae (I) and (II), B represents a single
bond or a straight chain alkylene group containing 1-4
carbon atoms. The straight chain alkylene group may have
ore or more substituents such as alkyl having 1-4 carbon
atoms (e.g., methyl, ethyl or propyl), aryl (e.g.,
25 phenyl) which may have one or more substituents (e.g.,
alkyl such as methyl or ethyl, alkoxy such as methoxy or
ethoxy, or halogen such as fluorine, chlorine or brom-
ine), aralkyl (e.g. benzyl) which may have one or more
substituents as mentioned for the possible substituents
30 of the alkyl, hydroxy and oxo. In the piperazine deriva-
tive of the invention, B preferably is a straight chain
alkylene having 1-4 carbon atoms which may have one or
more substituents selected from the group consisting of
phenyl benzyl, hydroxy and oxo.
- _ - 8 - 133~768
In the formulae (I) and (II), R represents hydrogen,
alkali metal (e.g., sodium or potassium), alkaline earth
metal (e.g., calcium or magnesium), alkyl having 1-6 car-
bon atoms (e.g., methyl, ethyl, propyl or butyl), cyclo-
5 alkyl (e.g., cyclopentyl or cyclohexyl), aralkyl (e.g.,benzyl or benzhydryl), or aryl (e.g., phenyl, tolyl or
xylyl). In the invention, R preferably is alkyl.
In the formulae (I) and (II), "n" is 2 or 3, and "n"
preferably is 2.
Preferred groups and atoms for "A", "A1", B and R
are described below.
Each of "A" in the formula (I) and "A1" in the for-
mula (II) preferably is a phenyl group having at least
one substituent selected from the group consisting of
15 hydroxy, alkoxy, acyloxy, amino, alkylamino, alkylthio,
halogen, alkyl and nitro.
Further, each of "A" in the formula (I) and "A1" in
the formula (II) preferably is a phenyl group having at
least one substituent selected from the group consisting
20 of hydroxy and alkoxy and additionally having at least
one substituent selected from the group consisting of
halogen, alkyl, fluoroalkyl, formyl, alkoxycarbonyl,
acyl, acyloxy, glycosyloxy, amino, alkylamino, mercapto,
alkylthio, and nitro.
Furthermore, each of "A" in the formula (I) and "A "
in the formula (II) preferably is a p-benzoquinonyl or
cumarinyl group which have at least one substituent
selected from the group consisting of alkyl and alkoxy.
The piperidine derivatives of the formulae (I) and
30 (II) in which R is hydrogen, alkyl, cycloalkyl, aryl or
aralkyl may be produced in the form of their pharmaceu-
tically acceptable addition salt. Such addition salts
can be prepared using hydrochloric acid, hydrobromic
acid, sulfuric acid, furaric acid, maleic acid or tar-
35 taric acid. Other inorganic or organic acids can be
~ 337768
employed, so long as such acids can give pharmacological-
ly acceptable salts with the piperizine derivatives of
the invention.
The piperizine derivatives of the formulae (I) and
5 (II) can be prepared, for instance, by the following
processes.
(1)
H0-A + formaldehyde(HCH0) + H-N N-C-S-Ra
(or HCH0 doner) ~CH2~n -
(III) (IV)
/ \ ll a
H0-A-CH2-N N-C-S-R
~cH2~Jn
In the above equation, A represents a phenyl or
cumarinyl group which may have at least one substituent
such as halogen, alkyl, fluoroalkyl, formyl, alkoxycar-
bonyl, acyl, hydroxy, alkoxy, acyloxy, glycosyloxy,
amino, alkylamino, mercapto, alkylthio and nitro; Ra is
20 hydrogen, alkyl, cycloalkyl, aralkyl and aryl; and n is 2
or 3.
The reaction of the compounds of the above formulae
(III) and (IV) and formaldehyde (or formaldehyde doner)
can be performed under appropriate conditions according
25 to the known Mannich reaction. In the equation, a
piperazine derivative of the formula (IV) may be in the
form of an addition salt such as hydrochloride.
Formaldehyde (or formaldehyde doner) may be used in the
form of aqueous formalin or paraformaldehyde. The
30 reaction according to the equation can be carried out in
water, an alcoholic solvent such as methanol or ethanol,
an organic acid such as acetic acid, an etheral solvent
such as ether or dioxane, or other polar solvent such as
- -- lo - 1 337768
dimethylformamide (DMF) or acetonitrile at a temperature
ranging from 0C to the boiling point of the used
solvent.
Alternatively, an active compound produced by a
5 reaction of a piperazine derivative of the formula (IV)
and formaldehyde can be caused to react with a compound
of the formula (III) to yield a compound of the formula
(I). The above-mentioned active compound can be repre-
sented by one of the following formulae:
1 0 / \ S
H0-CH2-N N-C-S-Ra --- (IVa)
\~ CH2~Jn
C~-CH2-N N-C-S-Ra --- (IVb)
15 ~CH2~n
a ISI / \ / ~ S a
R -S-C-N N-CH2-N N-C-S-R --- (IVc)
~ CH2~n ~ CH2~Jn
In the above formulae, each of Ra and "n" has the
20 same meaning as above.
(2)
~ S~ SI
A -B-Q + H-N N-C-S-R , A -B-N N-C-S-R
~CH2~n ~CH2~n
25(V) (VI)
In the above formulae, Q is a releasable group, and
each of A1, B, R and "n" has the same meaning as above.
In the above equation, the reaction between a com-
pound of the formula (V) and a piperazine derivative of
-- 11 1 337768
the formula (VI) can be performed in an inert solvent
such as ethanol, acetone, methylene chloride or DMF in
the presence of a base such as sodium carbonate, potas-
sium carbonate, sodium hydroxide or triethylamine. The
5 reaction can be carried out at a temperature of 0C to
the boiling point of the employed solvent. The reaction,
alternatively, can be performed under heating to 50 to
250C in the absence of a solvent. Examples of the
releasable groups represented by Q1 include halogen atoms
10 such as chlorine and bromine and tosyloxy group.
(3)
\ H CS MOH ~ A1 l ~ S
~CH2~n ~CH2~n
(VII) (VIII)
In the above formulae, M is an alkali metal or an
alkaline earth methal, and each of A1, B, and "n" has the
same meaning as above.
In the above equation, a piperazine derivative of
20 the formula (VII) is caused to react with hydroxide of an
alkali metal or an alkaline earth metal and carbon disul-
fide in an inert solvent such as ether, chloroform,
methanol or tetrahydrofuran at a temperature of -10C to
the boiling point of the employed solvent, preferably at
25 a temperature of 0 to 30 C. If the reaction is performed
using neither hydroxide of alkali metal nor alkaline
e~rth metal, a piperazine derivative of the formula
(VIII) is obtained in the form where the alkali metal or
alka~ine earth metal is replaced with hydrogen.
_ 12 -
(4) l 337768
A1-B-N N-C-S-M + Rb-Q2 ~ Al B N ~ -C-S-Rb
~CH2~n ~CH2~n
(VIII)
In the above formulae, Q2 is a releasable group, Rb
is alkyl, cycloalkyl, aralkyl or aryl, and each of A1, B,
M and "n" has the same meaning as above.
In the above equation, the reaction can be performed
10 in an inert solvent such as methanol, ethanol, DMF,
tetrahydrofuran, chloroform or benzene at a temperature
of -10C to the boiling point of the employed solvent,
preferably at a temperature of 0 to 30C. Examples of
the releasable groups represented by Q include halogen
15 atoms such as chlorine, bromine and iodine, p-toluenesul-
fonyloxy and methansulfonyloxy. Even if a piperazine
derivative of the formula (VIII) where the alkali metal
o- alkaline earth metal is replaced with hydrogen is used
as the starting compound, the reaction can be carried out
20 in the presence of an alkali metal in a similar manner.
(S)
(R 0)i-A -B-N N-C-S-R -i~ (H0)i-A2-B-N S
~CH2~n ~CH2~n
(IX)
In the formulae, R1 is alkyl, "i" is an integer of 1
to 5, A corresponds to the aforementioned "A" except for
excluding both the alkoxy- and alkoxycarbonyl-substituted
groups, and each of B, R and "n" has the same meaning as
30 above.
- 13 -
~ 33776~
In the above equation, the reaction can be performed
by cleaving the ether group of the piperizine derivative
of the formula (IX) using an appropriate reagent to con-
vert the alkoxy group (which is attached to the group
5 "A ") into hydroxy. Examples of the reagent for cleaving
the ether group include boron tribromide, hydrobromic
acid, trimethylsilane iodide and pyridine hydrochloride.
Preferred is boron tribromide. If boron tribromide is
employed in the reaction, the reaction can be performed
10 in an alkyl halide solvent such as methylene chloride or
chloroform at a temperature of -70 C to 30 C, preferably
at a temperature of -50C to 0C for a period of time of
1 hr. to 5 days, preferably for a period of time of 5
hrs. to 2 days.
(6)
(Ho)i-A3-B-N N-C-S-R --~ (R20) A3 B N ~ N-C-S-R
~cH2~Jn ~CH2t~n
(X)
In the above formulae, R2 is alkyl or acyl, Q3 is a
releasable group "i" is an integer of 1 to 5, A3 corre-
sponds to the aforementioned "A1" except for excluding
the hydroxy-substituted group, and each of B, R and "n"
has the same meaning as above.
In the above equation, the reaction can be performed
by converting the hydroxy group attached to the group of
"A3" of the piperizine derivative of the formula (X) into
alkoxy or acyloxy. The reaction can be carried out by acyl-
ating or alkylating the piperizine derivative of the for-
30 mula (X) in an inert solvent such as chloroform using an
appropriate reagent. The acylating reagent may be acetic
anhydride and the alkylating reagent may be dialkylsul-
furic acid.
- _ - 14 -
1 337768
(7)
1l ~ ISl R3 ~ S
A-B -C-B -N N-C-S-R > A-B -C-B -N N-C-S-R
~CH2~n H ~CH2~n
(XI)
In the formulae, each of B1 and B2 independently is
a straight chain alkylene group having 1-3 carbon atoms
which may be substituted with alkyl, aryl or aralkyl but
is not substituted with hydroxy or oxo, provided that the
10 total number of carbon atoms contained in the straight
chain alkylene groups of B and B2 does not exeed 4 (B1
may be a simple linking bond), R3 is hydroxy or hydrogen,
and each of A, R and "n" has the same meaning as above.
In the above equation, the reaction can be performed
15 by reducing the >C=0 group of the piperizine derivative
of the formula (XI) in a solvent generally employable for
reducing reactions using a reducing agent. Examples of
the solvent include methanol, ethanol and tetrahydrofuran
(THF). Examples of the reducing agent include sodium
20 borohydride, and sodium borohydride-aluminum chloride.
(8)
A-B3-CooH + H-N N-8-S-Ra----~A-B3-C-N ~ -C-S-Ra
~CH2 3Jn ~ CH2~/n
(XII)
In the above formulae, B3 is a simple linking bond
or a straight chain alkylene group having 1-3 carbon
atoms which may be substituted alkyl, aryl, aralkyl,
hydroxy or oxo, and each of A, Ra and "n" has the same
30 meaning as above.
- _ - 15 - l 337768
In the above equation, the reaction is performed by
subjecting a carboxylic acid of the formula (XII) and the
piperazine derivative to dehydrating condensation. The
dehydrating condensation can be carried out using a known
5 condensating agent such as dicyclohexylcarbodiimide.
Alternatively, the condensation can be carried out after
converting the carboxylic acid into its reactive deriva-
tive.
In addition, the piperazine derivative of the for-
10 mula (I) can be prepared by the following process.
(9)
OH O
~ ~ S HCl-FeC13 ~ ,~ I
¦ ~ B-N N-C-S-R > ~ ~ B-N -C-S-R
y ~CH2~n oxidation ~ ~CH2~n
OH (XIII) o
In the above equation, the reaction is performed em-
ploying an oxidizing agent such as FeC~3. Also employ-
able are nitric acid, silver oxide, lead tetraacetate,
20 alkaline salts of dichromic acid and lead oxide.
Representative examples of the piperazine derivative
of the formula (I) are set forth in the following Table 1
and Table 2. In the Tables, each symbol means the fol-
lowing group: Me: methyl, Et: ethyl, Pr: propyl, cy-hex:
25 cyclohexyl, Ph: phenyl, Ac: acetyl, and Glu: glucopyrano-
syl.
_ 16 -
1 337768
Table 1
R2 Rl
R3 ~ ~CH2 ~n
No. Rl R2 R3 R4 R5 B n R
1 H H H H H CH2 2 Me
2 Cl H H H H CH2 2 Me
10 3 Me H H H H CH2 2 Me
4 OH H H H H CH2 2 Me
5 -OMe H H H H CH2 2 Me
6 H OMe H H H CH2 2 Me
7 H H OMe H H CH2 2 Me
15 8 SH H H H H CH2 2 Me
9 SMe H H H H CH2 2 Me
No2 H H H H CH2 2 Me
11 NH2 H H H H CH2 2 Me
12 NHMe H H H H CH2 2 Me
13 NMe2 H H H H CH2 2 Me
14 OAc H H H H CH2 2 Me
OH OH H H H CH2 2 Me
16 OH H H OH H CH2 2 Me
17 OH H H H OH CH2 2 Me
25 18 OH OMe H H H CH2 2 Me
19 OH H OMe H H CH2 2 Me
OH H H OMe H CH2 2 Me
21 OH H H OAc H CH2 2 Me
22 OMe OMe H H H CH2 2 Me
1 3377~8
- 17 -
23 OMe H H OMe H CH2 2 Me
24 OMe H H H OMe CH2 2 Me
OMe H Me H H CH2 2 Me
26 OMe H CF3 H H CH2 2 Me
5 27 OMe H H H Me CH2 2 Me
28 OMe H Cl H H CH2 2 Me
29 OMe H H Ac H CH2 2 Me
SMe H H OMe H CH2 2 Me
31 H OMe OMe H H CH2 2 Me
10 32 OH OH OH H H CH2 2 Me
33 OMe OMe OMe H H CH2 2 Me
34 OAc OAc OAc H H CH2 2 Me
OH OMe OMe H . H CH2 2 Me
36 OMe H OMe H OMe CH2 2 Me
15 37 OH H OMe H OMe CH2 2 Me
38 OH OMe H CHO H CH2 2 Me
39 OH OH C2Me -H CH2 2 Me
H OH OH OH H CH2 2 Me
41 H OMe OMe OMe H CH2 2 Me
42 H OAc OAc OAc H CH2 2 Me
43 H OMe OH OMe H CH2 2 Me
44 OH OH OH H C02Pr CH2 2 Me
OMe OMe OMe H C02Pr CH2 2 Me
46 OH Me Me OH Me CH2 2 Me
47 OH OMe OMe OH Me CH2 2 Me
48 OAc OMe OMe OAc Me CH2 2 Me
49 OH H H H H CO 2 Me
OH H H OH H CO 2 Me
51 OMe H H H H CO 2 Me
30 52 SMe H H H H CO 2 Me
53 OMe OMe H H H CO 2 Me
54 OMe H OMe H H CO 2 Me
OMe H H OMe H - CO 2 Me
56 OMe OMe OMe H H CO 2 Me
57 H OMe OMe OMe H CO 2 Me
- 18 -
1 337768
58 H -OCH20- H H CO 2 Me
59 NH2 H H H H CO 2 Me
60 NMe2 H H H H CO 2 Me
61 OAc OAc OAc H H CO 2 Me
5 62 OMe OMe OMe H H CO 2 Et
63 OMe H H CH2CH2 2 Me
64 OH H H 2CH2 2 Me
65 OMe H H CQ H2CH2 2 Me
66 OMe H H OAc 2CH2 2 Me
67 OMe OMe OMe H H CH2CH2 2 Me
68 OH OH OH 2 2 2 Me
69 OMe OMe OMe H H - 2 Me
H OMe OMe OMe H - 2 Me
71 OMe OMe OMe H H COCH2 2 Me
15 72 H OH OH H H COCH2 2 Me
73 H OH OH H H CH(OH)CH2 2 Me
74 H OMe OMeOMe H COCH2 2 Me
75 OMe OMe OMe H H CH2C0 2 Me
76 H OH OH H H CH2C0 2 Me
77 OH H H H H CH2C0 2 Me
78 NH2 H H H H CH2C 2 Me
79NMe2 H H H H CH2C 2 Et
H -OCH20- H H CH2C 2 Me
81 OMe H H H H CH2CH2CH2 2 Me
82 OMe OMe OMe H H CH2CH2CH2 2 Me
83 OH H H OH H CH2CH2C0 2 Me
84 OMe OMe OMe H H CH2CH2C0 2 Me
H -OCH20- H H CH2CH2C0 2 Et
86 OH H H H H CHOHCH2C0 2 Me
87 OMe OMe OMe ( 2)3Co 2 Me
88 OMe OMe OMe H H CH2 3 Me
89 H OMe OMe OMe H CH2 2 Na
90 OMe OMe OMe H H CH2 2 Na
91 OMe OMe OMe H H CH2 2 K
35 92 OH OH OH H H CH2 2 H
19 - ~ 3 3 1 7 ~ ~
93 OMe OMe OMe H H CH2 2 H
94 H OMe OMe OMe H - 2 H
OMe OMe OMe H H CH2 2 Et
96 H OMe OMe OMe H CH2 2 i-Pr
5 97 OMe OMe OMe H H CH2 2 Pr
98 OMe H H H H CH2 2 cy-hex
99 H OMe OMe OMe H CH2 2 CH2Ph
100 OH OH OH H H CH2 2 CH2Ph
101 OMe OMe OMe H H CH2 2 Ph
10 102 H H H H H CHPh 2 Me
103 OMe H H H H CHPh 2 Me
104 OH H H H H CHPhCH2 2 Me
105 OMe H H H H CH(CH2Ph) 2 Me
106 OH OH H -CH=CHC02- CH2 2 Me
15 107 OH OGlu H -CH=CHC02- CH2 2 Me
108 H OMe OMe OMe H CH2 2 H
109 H OH OH OH H CH2 2 H
Table 2
O S
~ ~CH2~n
No. R1 R2 R3 B n R
1 337768
- 20 -
110 H H H ~H2 2 Me
111 Me H H CH2 2 Me
112 Me Me H CH2 2 Me
113 Me Me Me CH2 2 Me
5 114 H H H2CH2 2 Me
115 H H H CH2C0 2 Me
116 Me Me Me CH2 3 Me
117 Me Me Me CH2 2 Pr
118 OMe OMe Me CH2 2 Me
10 119 OMe OMe Me CH2 2 CH2Ph
120 OMe OMe Cl CH2CH2CH2 2 Me
The inhibitory action on lipid peroxidation of the
piperazine derivtives of the invention is illustrated by
the following pharmacological experimental data. Fur-
15 ther, the preventive action on deviation of GOT value and
GPT value determined using acute liver disease model in
vivo is shown below.
Experiment 1: Inhibitory Action on Lipid Peroxidation
1. Experimental procedure
A hepatocyte was isolated from rat according to the
method of U1 et al (Hiroshi Oka and Tadao Ui: "Isolated
Cells - Experimental and Application", page 91). The
determination of lipid peroxidation was performed using a
died hepatocyte which had been freezed at -85 and
25 stored at the temperature and which was melted when the
experimental was done.
To 50 ~1 of a hepatocyte dispersion (amount of pro-
tein: 0.5-1.0 mg) in a centrifugal tube were successively
added 5 ~ of a DMSO (dimethylsulfoxide) solution of the
30 sample compound, 50 ~l of ADP solution (40 mmol.), 50 ~l
of NADPH solution (4 mmol.) and 350 ~ of Tris(0.5 mol.)-
- 21 - l 3 3 7 7 6 8
hydrochloric acid buffer (pH 7.4). The centrifugal tube
was shaken at 37 C for 1 hour for performing a reaction,
and then placed into an ice-water bath to terminate the
reaction. To the content of the centrifugal tube were
5 added 0.2 ml of 8.1% aqueous SDS (sodium dodecylsulfon-
ate) solution, 50 ~ of ethanol solution of BHT (2,6-di-
tert-butyl-p-cresol, 5,000 ppm), 1.8 ml of 20% acetic
acid (pH 3.5) and 1.5 ml of 0.8% TBA (thiobarbituric
acid) solution (pH 3.5). The centrifugal tube was taken
10 out of the ice-water bath and placed in a water bath
(kept at 95-98C). The content of the tube was heated in
the bath for 1 hour for developing color-formation.
After the heating was complete, the content of the tube
was cooled and subjected to centrifugal separation. The
15 inhibitory action on lipid peroxidation of the sample was
determined by measuring absorbance at 530 nm. The deter-
mined inhibitory action is expressed inhibition ratio by
percent (/0) calculated by the following equation:
Inhibition Ratio (%) = [1 - (absorbance of tested
compound-applied group - absorbance of blank
group)/(absorbance of control group -
absorbance of blank group)] x 100
Remark: To the control group was applied (added)
DMS0 only.
25 2. Results
The results of the determination are set forth in
Table 3. In Table 3, the number of the tested compound
corresponds to the identical number set forth in Tables 1
and 2 for identifying the compounds of the invention.
- 22 - l 3 3 7 7 6 8
Table 3
No. of Tested Inhibition Ratio (at Final Concentration
of Tested Compound)
Compound
10-4 M 1O-sM
89 90.2 % ---
92.6 ___
106 89.0 88.1 %
72 74.8 58.2
1073 88.4 44.5
108 72.6 39.2
42 71.6 71.6
16 73.4 69.4
32 87.8 87.4
15109 74.9 24.2
4 100 96.6
44 96.6 96.0
13 98.9 95.4
22 100 92.0
2047 ` 100 56.1
23 100 60.6
11 98.6 95.5
48 96.2 97.5
It is apparent from the results given in Table 3
25 that the piperazine derivatives of the present invention
show excellent inhibitory action on enzymic lipid per-
oxidation in vitro.
1 337768
- 23 -
Experiment 2: Preventive Action on Deviation of GOT
Valu~ and GPT Value In Vivo Using Model
of Acute Liver Disease Caused by CC~
1. Experimental procedure
CC~4 in olive oil (concentration: 50 %) was orally
administered to a Wister-strain rat (body weight: 170 -
180 g) fasted for 24 hrs., at a dose of 1 ml/kg, to cause
acute liver disease. The piperazine derivatives of the
invention to be tested were administered in a dose of 30
10 mg/kg at 3 hour in advance of the administration of CC4.
For control group, 1.0 % methylcellulose (MC) was admini-
stered in place of the piperazine derivative. For normal
group, a simple olive oil was administered in place of
the CC~4-containing olive oil. For the administration,
15 the piperazine derivative was employed in the form of a
dispersion in aqueous MC solution (concentration: 1.0 ~0).
At 24 hours after the administration of CC~4, the
rat was abdominally sectioned under ether anesthesia.
From the abrominal large vein, a blood was collected.
20 The collected blood was subjected to centrifugal sepa-
ration at 3,000 r.p.m. for 10 min to obtain its plasma.
The plasma was then analyzed in an autoanalyzer (Hitachi
705, tradename) for biochemically assaying GOT value and
GPT value according to Karmen method.
The results are set forth in Table 4 in terms of a
ratio (%) of suppresion (prevention) of GOT or GPT. In
Table 4, "***" means 90-100 %, "**" means 60-90 %, and
"*" means 30-60 %. The number of the tested compound
corresponds to the number set forth in Tables 1 and 2.
The ratio of suppression is calculated according to
the following equation.
Ratio of suppresion = ~1 - (value of sample-
administered group - value of normal group)/(value
of control group - value or normal group)] x 100
- 24- ~337768
Table 4
No. of Compound GOT GPT
* *
2 *
3 ** **
4 *** ***
*** ***
6 *** ***
7 ** *
1 0 9
** *
1 1 *** ***
13 * *
16 *** ***
18
21 ** *
22
23 *** ***
31
32 ** **
33
34 _ *
** **
37 **
38 **
44 ***
46 *** ***
47 *** ***
48
- 25 ~l 3 3 7 7 6 8
56 **~ ~**
67 *
68 ** **
71 **
73 ** **
**
93 *** ***
100 - *
110 *** ***
113 *** **
118 **
When liver cells are damaged by the administration
of CC~4, enzymes contained in the celles are released
into a blood, and various enzymic activities are observed
15 in a serum obtained from the blood. Accordingly, it is
known that a degree of damage of liver can be effectively
determined by measuring serum transaminases such as GOT
(glut~mic-oxaloacetic transaminase) or GPT (glutamic-
pyruvic transaminase). The above experiments were per-
20 formed based on the above knowledge.
As is seen from the results of the above-given
Experiment 2, the piperazine derivatives of the invention
significantly well suppress increase of amounts of GOT
and/or GPT which are known to indicate the degree of
25 liver damange.
From the pharmacological experimental results given
above, it is established that the piperazine derivatives
of the invention show excellent inhibitory effect on
lipid peroxidation, as well as effective preventive (or
3Q suppressive) action on deviation of values of GOT and/or
GPT in acute liver damage model in vivo.
Further, it has been experimentally confirmed that
all of piperazine derivatives of the invention tested for
- 26 - i ~ 3 7 7 68
toxicity (Compound Nos. 4, 5, 22, 23, 32, 33, 38, 75 and
113 indicated in Tables 1 and 2) cause no death even at
1,600 mg/kg by oral administration.
The therapeutic agent of the present invention can
5 be generally prepared in the form of a pharmaceutical
composition in combination with an appropriate pharma-
ceutical carrier. Examples of the carrier include dilu-
ents such as filler, binder, disintegrating agent, and
lubricant, vehicles, and excipients. The therapeutic
10 agent of the invention can be orally or parenterally
administered in the form of in~ection liquid, powder,
capsules, granules, or pellets. The dose of the thera-
peutic agent of the invention varies with conditions and
age of patients. Ordinarily, the piperazine derivative
15 of the invention is administered into a patient at a dose
of approx. 10 mg to 1 g per day.
Thus, the above-identified piperazine derivative
having the formula (I) and its pharmaceutically accept-
able salt show favorable action in in-vivo tests for
20 treatment acute liver disease caused by carbon tetra-
chloride for inhibition or suppresion of deviation of
values of GOT (glutamic oxaloacetic transaminase) and GPT
(glutamic pyruvic transaminase).
Accordingly, the piperazine derivative of the for-
25 mula (I) and its pharmaceutically acceptable salt accord-
ing to the invention are well effective for prevention or
treatment (including tratment for suppresion of disease)
of liver disease. Further, the piperidine derivative of
the formula (I) and its pharmaceutically acceptable salt
30 show inhibitory effect on lipid peroxidation and are
active as therapeutic agents for preventing or treating
inflammation, rheumatism, disease of digestive tract.
The following examples further illustrate the
present invention. In the examples, the compound number
- _ - 27 - l 337768
given at the end of each compound corresponds to the
piperazine derivative set forth in Tables 1 and 2.
Example 1
i) 3,4,5-Trimethoxybenzyl chloride
In 40 ml of benzene was dissolved 10 g of 3,4,5-tri-
methoxybenzyl alcohol. To the resulting solution was
dropwise added under chilling with ice 10 ml of benzene
solution containing 7.6 g of thionyl chloride. After the
addition was complete, the mixture was stirred at room
10 temperature for 15 min. The reaction solution was poured
into a chilled aqueous potassium carbonate, and a sepa-
rated benzene portion was collected. The benzene portion
was washed with a saturated aqueous sodium chloride solu-
tion, dried over anhydrous sodium sulfate and placed
15 under reduced pressure to distill off the solvent. The
desired compound was obtained as a yellow solid (yield:
11.0 g).
ii) 1-(3,4,5-Trimethoxybenzyl)piperazine
A mixture of 4.48 g of piperazine (6 hydrates) and
20 10 ml of ethanol was warmed at 65-70C to give a homoge-
neous solution. To the solution were added 4.09 g of
piperazine?2HCl H20 and 5 ml of ethanol. At the same
temperature, 5.0 g of 3,4,5-trimethoxybenzyl chloride and
15 ml of ethanol were further added at once. The result-
25 ing mixture was stirred at 65-70 C for additional 30 min.
and then chilled with ice. A precipitated insoluble was
rmoved by filtration, and the resulting mother liquer was
concentrated. To the concentrated mother liquer was
added 8 ml of ethanolic 6-N hydrochloric acid. The mix-
30~ture was stirred for 30 min under chilling with ice.Precipitated crystals were collected by filtration,
washed with ethanol and dried to give hydrochloride of
the desired compound.
~ - 28 - l 33776~
The obtained hydrochloride was dissolved in 15 ml of
water. The solution was made alkaline by addition of
aqueous 1-N sodium hydroxide. The alkaline solution was
extracted seven times with chloroform after salting-out.
5 The chloroform extracts were combined, dried over anhy-
drous sodium sulfate, and placed under reduced pressure
to distill off the solvent, to give 4.93 g of the desired
compound as a pale yellow crystalline powder.
iii) Sodium 4-(3,4-5-trimethoxybenzyl)-1-piperazine-
carbodithioate (Com. No. 89)
To 50 ml of ether solution containing 4.9 g of 1-
(3,4,5-trimethoxybenzyl)piperazine was added under chil-
ling with ice 1.01 g of sodium hydroxide in 1.5 ml of
water. To the solution was further added dropwise under
15 chilling with ice 13 ml of ether solution containing 1.81
g of carbon disulfide. The resulting mixture was stirred
overnight at room temperature. Thus precipitated cry-
stals were collected by filtration, washed with ether and
dried under reduced pressure to give 6.67 g of the
20 desired compound as a white powder, m.p. 119-122C.
H-NMR (CD30D)~ : 2.30 - 2.60 (m, 4H), 3.46 (s, 2H),
3.76 (s, 3H), 3.84 (s, 6H), 4.3 -
4.6 (m, 4H), 6.64 (s, 2H)
IR (KBr) cm 1 3380, 1590, 1460, 1420, 1220, 1130
Example 2
i) Methyl 4-(3,4,5-trimethoxybenzyl)-1-piperazine-
carbodithioate
To 70 ml of methanol containing 6.67 g of sodium 4-
(3,4,5-trimethoxybenzyl)piperazinecarbodithioate was
30 dropwise added under chilling with ice 20 ml of methanol
solution containing 2.6 g of methyl iodide for 20 min.
The resulting mixture was further stirred for 3 hours
under chilling with ice. The reaction solution was
~ - 29 - 1 337~68
placed under reduced pressure to distill off the solvent,
leaving a residue. The residue was dissolved in water,
and then extracted with chloroform. The chloroform por-
tion was washed with a saturated aqueous sodium chloride
5 solution, dried over anhydrous sodium sulfate, and placed
under reduced pressure to distill off the solvent. Thus
obtained crude product was purified by silica gel chro-
matography to give 3.7 g of the desired compound as a
pale yellow crystalline product.
1H-NMR (CDCl3)~ : 2.40 - 2.60 (m, 4H), 2.66 (s, 3H),
3.46 (s, 2H), 3.84 (s, 3H),
3.86 (s, 6H), 3.9 - 4.3 (m, 4H),
6.55 (s, 2H)
MS (m/e): 356 (M+), 341, 309
ii) Methyl 4-(3,4,5-trimethoxybenzyl)-1-piperazine-
carbodithioate-hydrochloride (Com. No. 41)
m.p.: 212.5 - 214C (decomp.)
H-Nr.IR (CD30D)~ : 2.65 (s, 3H), 3.1 - 3.7 (m, 6H),
3.78 (s, 3H), 3.90 (s, 6H),
4.33 (s, 2H), 4.9 - 5.5 (m, 2H),
6.94 (s, 2H)
IR (KBr) cm 1 2400, 1590, 1460, 1420, 1325, 1270,
1250, 1120, 950
Example 3
Methyl 4-(3,4,5-trihydroxybenzyl)-1-piperazine-
carbodithioate (Com. No. 40)
To 100 ml of methylene dichloride was added 2.6 ml
of boron tribromide, and the resulting mixture was
chilled to -40C. To this mixture was further dropwise
30 added 50 ml of methylene chloride containing 2 g of 4-
(3,4,5-trimethoxybenzyl)-1-piperazinecarbodithioate for
approx. 30 min. The reaction mixture was stand for
~ _ 30 _ l 3 3 7 7 ~' ~
reaching room temperature, and stirred overnight at room
temperature. To the mixture was then added portionwise
water under chilling with ice. A resulting precipitate
was collected, washed successively with water and ace-
5 tone, and dried under reduced pressure at room tempera-
ture. The dried product was dissolved in a small amount
of methanol. Water was added to the methanol solution to
give a precipitte. The precipitate was collected by fil-
tration and dried under reduced pressure to give 450 mg
10 of hydrobromide of the desired compound as a pale red
powder, m.p. 158 - 160C (decomp.).
H-NMR (CD30D)~: 2.64 (s, 3H), 3.0 - 3.7 (m, 6H),
4.16 (s, 2H), 4.8 - 5.6 (m, 2H),
6.53 (s, 2H)
15 IR (KBr) cm 1 3125, 1625, 1545, 1450, 1420, 1340,
1255, 1025
Example 4
4-(3,4,5-Trimethoxybenzyl)-1-piperazine-
carbodithioic acid (Com. No. 108)
In an aqueous 10% sodium hydroxide solution was
dissolved 1.40 g (4.13 mmol.) of 3,4,5-trimethoxybenzyl-
1-piperazine-dihydrochloride. The solution was then
extracted with chloroform. The chloroform portion was
dried over anhydrous sodium sulfate and placed under
25 reduced pressure to distill off the solvent, to give 933
mg (yield: 90.3 ~) of a free amine product as a white
crystalline product.
The obtained product was dissolved in 3 ml of
methanol. The solution was stirred at room temperature
30 for 1 hour after dropwise addition of 0.25 ml (4.1 mmol.)
of carbon dusulfide. Insolubles were removed by filtra-
tion and washed with methanol to give a pale yellow
powder. The powder was then dried under reduced pressure
- 31 - I 3377 68
to give 1,260 mg of the desired compound, m.p. 171 -
174C (decomp.), yield 98.7 %.
H-N~R (DMS0-d6)~ : 2.9 - 4.0 (m, 8H), 3.64, 3.77
(each s, 9H), 4.1 - 4.6 (m, 2H),
6.4 - 6.8 (m, 2H), 8.2 - 9.6
(br, lH)
IR (KBr) cm 1 3400, 2980, 2960, 2920, 2895, 2820,
2645, 2575, 2500, 1585, 1495, 1460,
1440, 1435, 1420, 1380, 1360, 1350,
1340, 1320, 1250, 1240, 1230, 1200,
1175, 1150, 1120, 1100, 1060, 1020,
1005, 990, 980, 960, 940, 915, 835,
820
Example 5
Methyl 4-(3,4,5-triacetoxybenzyl)-1-piperazine-
carbodithioate (Com. No. 42)
To 395 mg (1.0 mmol.) of methyl 4-(3,4,5-trihydroxy-
benzyl)-1-piperazinecarbodithioate was added 2 ml of dry
pyridine. To the resulting suspension was added 0.22 ml
20 (3.1 mmol.) of acetyl chloride under chilling with ice.
The mixture was then stirred, and further stirred
overnight at room temperature. The mixture was then
extracted with ethyl acetate after addition of water.
The extract was washed with a saturated aqueous sodium
25 chloride solution, dried over anhydrous sodium sulfate
and processed to distill off the solvent. The residue
was purified by silica gel column chromatography and
crystalliæed from ether to give 249 mg of the desired
compound as a whilte crystalline product, ~.p. 141 -
30 143C, yield 63.4 %.
H-NMR ~CDC~3)~ : 2.27 (s, 9H), 2.35 - 2.65 (m, 4H),
2.66 (s, 3H), 3.51 (s, 2H), 3.8 -
4.4 (m, 4H), 7.10 (s, 2H)
- _ - 32 - ~337768
IR (KBr) cm 1 2930, 2905, 2800, 1775, 1495, 1470,
1420, 1360, 1215, 1205, 1200, 1180,
1165, 1130, 1045, 1000, 890
Example 6
Methyl 4-(5-acetoxy-2-hydroxybenzyl)-1-piperazine-
carbodithioate (Com. No. 21)
To 5 ml of chloroform were added 152 mg of 4-acet-
oxyphenol, 211 mg of methyl 1-piperazinecarbodithioate
and 36 mg of paraformaldehyde. The resulting mixture was
10 refluxed for 4 hours. The mixture was cooled, and to
this was added chloroform. The mixture was then washed
with water and a saturated aqueous sodium chloride solu-
tion,dried over anhydrous sodium sulfate and placed under
reduced pressure to distill of the solvent. The residue
15 was purified by siica gel column chromatography to yield
an oil. The oil was crystallized by addition of ethanol.
The obtained crystals were collected by filtration to
give 224 mg of the desired compound as a white crystal-
line product, m.p. 124C, yield 65.9 %.
1H-NMR (CDC~3) ~ : 2.24 (s, 3H), 2.66 (s, 3H), 2.3 -
2.8 (m, 4H), 3.68 (s, 2H), 4.0 -
4.4 (m, 4H), 6.6 -7.0 (m, 3H)
IR (KBr) cm : 2810, 1750, 1490, 1425, 1370, 1250,
1230, 1215, 1195, 1145
Example 7
Methyl 4-(2,3,4-trihydroxybenzyl)-1-piperazine-
carbodithioate (Com. No. 32)
To a mixture of 0.15 ml (2.0 mmol.) of 37 % formalin
and and 4 ml of methanol was dropwise added under stir-
30 ring 2 ml of a methanol solution containing 353 mg (2.0mmol.)of metyl 1-piperazinecarbodithoate. The resulting
- _ - 33 -
1 33776~
mixture was stirred overnight at room temperature without
exposing to light, after addition of added 253 mg (2.0
mmol.) of pyrogallol. A precipitated solid was removed
by filtration, and the solvent of the filtrate was eva-
5 porated. To the residue was added chloroform. Afterremoving insolubles, the solvent was distilled off. The
residual solid was then washed with hot ethanol to give
210 mg of the desired compound as a pale brown powder,
yield 11.1 %.
1H-NMR (DMS0-d6) ~: 2.49 (s, 4H), 2.56 (s, 3H),
3.51 (s, 2H), 3.7 - 4.3
(br, 4H), 6.1 - 6.4 (m, 2H),
8.1 - 8.9 (br, 3H)
Example 8
4-(3,4,5-Trihydroxybenzyl)-1-piperazine-
carbodithioic acid (Com. No. 109)
In a nitrogen atmosphere, 1,033 mg (3.02 mmol.) of
4-(3,4,5-trimethoxybenzyl)- 1-piperazinecarbodithioic
acid was suspended in dry methylene chloride, and under
20 chilling to -78C in a dry ice-acetone bath, to this was
dropwise added 50 ml of methylene chloride solution con-
taining 3 ml of boron tribromide. The mixture was left
to slowly reach room temperature, and then stirred for 5
days at room temperatuere. To the reaction mixture was
25 added water, and insolubles were removed by filtration.
The insolubles were then washed with water, and thus
obtained yellow solid was dissolved in methanol. The
methanol solution was filtered to remove insoubles, and
the solvent of the filtrate was distilled off. To the
30 obtained yellow semi-oil was added ether, and insolubles
were removed by filtration. The filtrate was dried and
further purified by cellulose column chromatography
(Avicel, trademark, eluent: butanol/acetic acid/water
- _ - 34 -
1 337768
(10/1/1)). The eluate was treated to distill off the
solvent (eluent). To the residue was added ether, and
insolubles were removed by filtration. The solvent of
the filtrate was distilled off, leaving 103 mg of the
5 desired compound, m.p. higher than 250C, yield 11.4 %.
H-NMR (DMS0-d6)~ : 2.8 - 4.3 (m, lOH), 6.38
(s, 2H), 8.0 - 9.5 (br, 4H)
IR (KBr) cm 1 3400, 3325, 3105, 3000, 2920, 2840,
2760, 2700, 2550, 1610, 1530, 1450,
1430, 13g5, 1380, 1330, 1300, 1235,
1190, 1160, 1150, 1070, 1035, 1005,
940, 860
Example 9
Methyl 4-(2,3,4-triacetoxybenzyl)-1-piperazine-
carbodithioate (Com. No. 34)
In 520 ml of chloroform was suspended 50 g of methyl
4-(2,3,4-trihydroxybenzyl)-1-piperazinecarbodithioate,
and to the suspension was dropwise added under chilling
with ice 97.3 g of acetic anhydride over a period of 15
20 min. The mixture was then stirred for one hour. The
reaction mixture was washed successively with water and a
saturated aqueous sodium chloride solution, and dried
over anhydrous sodium sulfate. The sodium sulfate was
removed by filtration, and the filtrate was concentrated
25 under reduced pressure. The residual oil was crystal-
lized by addition of 250 ml of ethyl acetate. After
stirring for one hour, the crystals were collected by
filtration. The crystals were washed with ethyl acetate
to give 48.~ g of the desired compound as white crystals,
30 m.p. 148 - 150 C (decomp.), yield 69.7 %.
H-NMR (CDC~3) ~ : 2.27 (s, 9H), 2.3 - 2.6 (m, 4H),
2.65 (s, 3H), 3.44 (s, 2H), 3.8 -
4.3 (br, 4H), 7.13 (d, lH,
- _ - 35 -
1 337768
J=8.6 Hz), 7.28 (d, lH, J=8.6 Hz),
IR (KBr) cm 1 2900, 2800, 1760, 1450, 1420, 1360,
1260, 1210, 1170, 1050, 1010, 910,
880, 820, 770
Example 10
i) Benzyl 1-piperazinecarbodithioate
To a solution of 0.8 g of sodium hydroxide in a mix-
ture of 9 ml of methanol and 1.2 ml of water was added
3.0 g of 1-piperazinecarbodithioic acid. The mixture was
10 stirred for 10 min., and placed under reduced pressure at
a temperature below 50C to distill off methanol and
water. To the residue was added 9 ml of methanol, and to
the resulting solution was dropwise added under chilling
with ice 3.1 g of benzyl bromide over a period of 20 min.
15 The mixture was then stirred for 15 min at room tempera-
ture. Insolubles were removed by filtration, and the
filtrate was placed under reduced pressure to distill off
the solvent. The residue was extracted with ether. The
ether extract was washed with water and an aqueous sodium
20 chloride solution, dried over anhydrous sodium sulfate,
and placed under reduced pressure to distill off the sol-
vent and to give 3.13 g of the desired compound as a pale
yellow oil, yield 67.0 %.
1H-NMR (CDC3) o: 1.72 (s, lH), 2.6 - 3.1 (m, 4H),
4.05 (br, 4H), 4.57 (s, 2H),
6.9 - 7.6 (m, 5H)
IR (neat) cm : 2950, 2900, 1460, 1420, 1250, 1220,
1130, 1020, 980, 750, 700
ii) Benzyl 4-(2,3,4-trihydroxybenzyl)-1-
piperazinecarbodithioate (Com. No. 100)
To a solution of 0.51 g of 35% formalin in 7.7 ml of
ethanol was added under chilling with ice a solution of
1.5 g of benzyl 1-piperazinecarbodithioate in 7.5 ml of
- 36 -
1 3377~8
ethanol. The mixture was stirred at room temperature for
10 min. To the mixture was further added under chilling
with ice a solution of 3.7 g of pyrogallol in 15.3 ml of
ethanol at once. The mixture was then stirred for 2.5
5 hours at room temperature. Ethanol was evaporated under
reduced pressure, and the residue was extracted with
dichloromethane. The dichloromethane solution was washed
with water and an aqueous sodium chloride solution, dried
over anhydrous sodium sulfate, and placed under reduced
10 pressure to distill off the solvent to give 2.17 g of the
desired compound as a pale red powder, m.p. 125 - 126C
(decomp.), yield 92.9 %.
H-NMR (CDC~3)~ : 2.4 - 2.8 (m, 4H), 3.64 (s, 2H),
4.14 (br, 4H), 4.52 (s, 2H),
6.11 (br, 3H), 7.0 - 7.4 (m, 7H)
Example 11
4-(2,3,4-Trimethoxybenzyl)-1-piperazine-
carbodithioic acid (Com. No. 93)
In 10 ml of methanol was dissolved 985 mg (3.7
20 mmol.) of trimethazidine, and to the mixture was dropwise
added under stirring at room temperature 0.23 ml of car-
bon disulfide for 25 min. The mixture was further stir-
red for 5 hours at room temperature. A precipitate was
collected by filtration and washed with methanol to give
25 1.11 g of the desired compound, m.p. 148 - 150C
(decomp.), yield 87.4 %.
H-N~R (DMSO-d6) ~ : 2.2 - 2.7 (m, 4H), 2.9 - 4.0
(m, 4H), 3.75 (s, 3H), 3.78
(s, 3H), 3.80 (s, 3H), 4.1 - 4.6
(m, 2H), 6.6 - 7.1 (m, 2H),
8.2 - 9.4 (br, lH)
IR (KBr) cm : 2975, 2900, 2810, 2780, 2700, 1600,
1490, 1460, 1440, 1410, 1380, 1350,
~ 37 - l 337 ~ ~8
1320, 1290, 1280, 1250, 1230, 1200,
1180, 1090, 1040, 1000, 960, 940,
920, 890, 850, 800, 780, 750, 690
Example 12
i) Methyl 4-(2,3,4-trimethoxybenzyl)-1-piperazine-
carbodithioate tCom. No. 33)
In a nitrogen atmosphere, 2.0 g of 4-(2,3,4-tri-
methoxybenzyl)-1-piperazinecarbodithioic acid, 0.26 g of
granular sodium hydroxide, and 3 ml of methanol were
10 mixed, and stirred at room temperature to yield a homo-
geneous reaction solution. To the solution was dropwise
added under chilling with ice a solution of 0.39 ml of
methyl iodide in 2.4 ml of methanol. After the addition
was complete, the reaction solution was stirred for 2.5
15 hours at room temperature. The solvent was then dis-
tilled off under reduced pressure, and chloroform and
water were added to the residue. The chloroform portion
was separated, washed with a saturated aqueous sodium
chloride solution, and dried over anhydrous sodium sul-
20 fate. The solvent was distilled-off under reduced pres-
sure to leave 2.0 g of the desired compound as a white
powder, yield 97.9 %.
H-NMR (CDC~3)~ : 2.4 - 2.7 (m, 4H), 2.65 (s, 3H),
3.51 (s, 2H), 3.86 (s, 3H),
3.87 (s, 6H), 3.8 - 4.3 (m, 4H),
6.63 (d, lH, J=8.6 Hz),
6.97 (d, lH, J=8.6 Hz)
ii) Methyl 4-(2,3,4-trimethoxybenzyl)-1-piperazine-
carbodithioate hydrochloride
To 1.6 g of methyl 4-(2,3,4-trimethoxybenzyl)-1-
piperazinecarbodithioate was dropwise added under chil-
ling with ice 9 ml of 1-N hydrochloric acid-ethanol. The
mixture was then stirred for 3 hours at room temperature.
~ 38 - 1 3377b8
Precipitated crystals were collected by filtration and
washed with ethanol to give 1.5 g of the desired hydro-
chloride as a white powder, m.p. 182 - 184C (decomp.),
yield 87.3 %.
1H-NMR (CDCl3) ~ : 2.65 (s, 3H), 2.6 - 3.1 (m, 2H),
3.2 - 3.8 (m, 2H), 3.87 (s, 3H),
3.88 (s, 3H), 3.95 (s, 3H),
3.9 - 4.2 (m, 2H), 4.22 (br, 2H),
4.8 - 5.4 (m, 2H),
6.7 (d, lH, J=8 Hz),
7.42 (d, lH, J=8 Hz)
IR (KBr) cm 1 2900, 2450, 1600, 1500, 1460, 1400,
1300, 1270, 1220, 1120, 1100, 1020,
960, 820
Example 13
i) Isopropyl 4-(3,4,5-trimethoxybenzyl)-1-
piperazinecarbodithioate (Com. No. 96)
In 2 ml of ethanol was suspended 364 mg of sodium
4-(3,4,5-trimethoxybenzyl)-1-piperazinecarbodithioate,
20 and to the suspension was added 204 mg of isopropyl
iodide. The resulting homogeneous solution was stirred
overnight at room temperature. Ethanol was distilled off
from the solution, and to the residue were added ether
and water. The ether portion was taken out, washed with
25 a saturated aqueous sodium chloride solution, dried over
anhydrous sodium sulfate, and placed under reduced pres-
sure to evaporate the solvent. The residue was purified
by silica gel column chromatography to give 270 mg of the
desired compound as a colorless oil, yield 70.3 %).
H-NM~ (CDCl3)6 : 1.41 (d, 6H, J=7 Hz), 2.3 - 2.7
(m, 4H), 3.45 (s, 2H), 3.8 & 3.85
(each s, 9H), 3.9 - 4.6 (m, 5H),
6.54 (s, 2H)
39 1 337768
_
ii) Isopropyl 4-(3,4,5-trimethoxybenzyl)-1-
piperazinecarbodithioate hydrochloride
In 2 ml of chloroform was dissolved 250 mg of the
above obtained product. To the solution was added 2 ml
5 of 1-N hydrochloric acid-methanol. The solvent was then
distilled off under reduced pressure. The residue was
crystallized from ethanol/diethyl ether. The crystals
were collected by filtration and washed with chilled
ethanol and diethyl ether to give 230 mg of the desired
10 compound as a white crystalline product, m.p. 210 -
212C, yield 84.1 %.
H-Nr~R (CDC~3)~ : 1.44 (d, 6H, J=8Hz), 2.5 - 3.1
(m, 2H), 3.3 - 4.4 (m, 7H), 3.84 &
3.92 (each s, 9H), 5.0 - 5.4
(m, 2H), 6.94 (s, 2H)
IR (KBr) cm : 2510, 2410, 1590, 1455, 1425, 1400,
1330, 1275, 1255, 1120, 945
Example 14
~ethyl 4-(2-hydroxy-5-methoxybenzyl)-1-piperazine-
carbodithioate (Com. No. 20)
To 20 ml of ethanol was 1.05 g of 37 % formalin, and
to the mixture was added under chilling with ice 2.29 g
of methyl 1-piperazinecarbodithioate. The mixture was
then stirred for 30 min. at room temperature, and, after
25 addition of 1.24 g of 4-methoxyphenol, refluxed overnight
under heating. The solvent was distilled off under
reduced pressure, and the residue was purified by silica
gel column chromatography. The obtained oil was cry-
stallized from 10 ml of ethanol. The crystals were
30 collected by filtration and subsequently washed with
ethanol to give 1.06 g of the desired compound as white
crystals, m.p. 112C, yield 34 %.
1H-NMR (CDC~3)~ : 2.65 (s, 3H), 2.5 - 2.8 (m, 4H),
- _ - 40 -
1 337768
3.68 (s, 2H), 3.73 (s, 3H), 3.9 -
4.4 (m, 4H), 6.4 - 6.9 (m, 3H),
9.5 (br, lH)
IR (KBr) cm : 1490, 1420, 1255, 1225, 1210, 1035,
995, 870, 735
Example 15
Methyl 4-(2,5-dihydroxybenzyl)-1-piperazine-
carbodithioate hydrochloride (Com. No. 16)
In 38 ml of ethanol was suspended 10.6 g of methyl
10 4-(5-acetoxy-2-hydroxybenzyl)-1-piperazinecarbodithioate
(co~.pound prepared in Example 6). In a nitrogen atmo-
sphere, 53 ml of conc. hydrochloric acid was added to the
suspension at room temperature. After the solid was dis-
solved, insolubles were removed by filtration, and fur-
15 ther the insolubles were washed with 4 ml of ethanol.The filtrate and washing were combined to give a pale
brown solution. The solution was stirred for 20 hours at
room temperature to give a suspension. The suspension
was further stirred at 80C for 3 hours, and then stirred
20 for 8 hours at room temperature. The crystalline solid
was collected by filtration and washed with ethanol to
give 6.34 g of the desired compound as a pale brown cry-
stalline powder, m.p. 200 - 202C (decomp.).
1H-N~R (CD30D)~ : 2.65 (s, 3H), 3.1 - 3.5 (m, 4H),
4.30 (s, 2H), 4.0 - 4.7 (m, 4H),
6.6 - 6.9 (m, 3H)
IR (KBr) cm 1 3200, 3000, 2830, 2700, 2580, 1500,
1450, 1435, 1415, 1380, 1335, 1320,
1260, 1230, 1200, 1190, 950, 835, 825
- 41 -
1 337768
Example 16
Methyl 4-(2-hydroxy-3-methoxybenzyl)-1-
piperazinecarbodithioate (Com. No. 18)
In 10 ml of ethanol was dissolved 0.86 g of 35 %
5 formalin. To the solution was dropwise added under chil-
ling with ice a solution of 2.35 g of methyl 1-pipera-
zinecarbodithioate in 5 ml of ethanol. The mixture was
then stirred for 30 min. at room temperature. The mix-
ture was refluxed overnight under heating after addition
10 of a solution of 1.24 g of 2-methoxyphenol in S ml of
ethanol under chilling with ice. The reaction mixture
was cooled to room temperature. Precipitated crystals
were collected by filtration and washed with 5 ml of
ethanol to give 1.44 g of the desired compound as a white
15 powder, m.p. 151 - 152C (decomp.), yield 45.9 %.
H-NMR (CDC~3)~ : 2.3 - 2.8 (m,-4H), 2.65 (s, 3H),
3.75 (s, 2H), 3.87 (s, 3H),
4.2 (br, 4H), 6.4 - 6.9 (m, 3H),
10 (br, lH)
IR (KBr) cm : 3450, 2580, 1580, 1460, 1420, 1230,
1140, 1070, 990, 960, 830, 770, 730
Example 17
Methyl 4-(6-propyloxycarbonyl-2,3,4-trihydroxy-
benzyl)-1-piperazinecarbodithioate (Com. No. 44)
In 10 ml of ethanol was dissolved 0.86 g (10 mmol.)
of 35 % formalin. To the solution placed in an ice bath
was further added a solution of 1.94 g (10 mmol., purity
90.7 %) of methyl 1-piperazinecarbodithioate in 4 ml of
ethanol. The resulting mixture was then stirred for 30
30 min. at room temperature. To the mixture placed in an
ice bath was dropwise added a solution of 2.12 g (10
mmol.) of propyl gallate in 4 ml of ethanol. The mixture
- -- ~ 3~ 7~ G 8
- 42 -
was stirred overnight at room temperature and subsequent-
ly refluxed under heating for 4 hours. The mixture was
cooled to room temperature. Precipitated crystals were
collected by filtration and washed with ethanol to give
5 1.843 g of the desired compound as a grayish powder, m.p.
142 - 144C (decomp.), yield 31.3 %.
H-NMR (CDC~3)~ : 0.99 (t, 3H, J=7 Hz), 1.5 - 1.9
(m, 2H), 2.4 - 2.8 (m, 4H),
2.66 (s, 3H), 3.9 - 4.4 (m, 8H),
5.0 - 5.6 (br, 3H), 7.08 (s, lH)
IR (KBr) cm 1 3380, 2960, 1700, 1600, 1460, 1420,
1340, 1260, 1230, 1100, 980, 780
Example 18
i) Methyl 4-(3,4-dimethoxy-2-hydroxybenzyl)-1-
piperazinecarbodithioate (Com. No. 35)
In 10 ml of ethanol was dissolved 0.86 g of 35 %
formalin. To the solution was dropwise added under chil-
ling with ice a solution of 2.35 g of methyl 1-pipera-
zinecarbodithioate in 5 ml of ethanol. The mixture was
20 then stirred for 30 min. at room temperature. The mix-
ture was refluxed overnight under heating after addition
of a solution of 1.54 g of 2,3-dimethoxyphenol in 5 ml of
ethanol under chilling with ice. The reaction mixture
was cooled to room temperature. The solvent was distil-
25 led off under reduced pressure, and the residue was puri-
fied by silica gel column chromatography. The eluate was
treated with 10 ml of ethanol to obtain a crystalline
product. The product was collected by filtration and
washed with ethanol to give 1.76 g of the desired com-
30 pound as a pale yellow crystalline product, m.p. 113C(decomp.), yield 51.5 %.
H-Nr~IR (CDC~3) S: 2.4 - 2.9 (m, 4H), 2.66 (s, 3H),
3.69 (s, 2H), 3.84 (s, 3H),
1 337768
~ - 43 -
3.88 (s, 3H), 4.2 (br, 4H),
6.35 (d, lH, J=8 Hz),
6.64 (d, lH, J=8 Hz)
ii) Methyl 4-(3,4-dimethoxy-2-hydroxybenzyl)-1-
piperazinecarbodithioate hydrochloride
In 1 ml of chloroform was dissolved 0.5 g of methyl
4-(3,4-dimethoxy-2-hydroxybenzyl)-1-piperazinecarbodi-
thioate. To the solution was dropwise added under chil-
ling with ice 1.46 ml of 1-N HCQ/ether mixture, and the
10 resulting mixture was stirred at room temperature. Pre-
cipitated crystals were collected by filtration and
washed with 6 ml of ether to give 0.53 g of the desired
compound as a white powder, m.p. 204 - 205C (decomp.),
yiled 95.9 /0.
1H-NMR (CDC~3/CD30D)~ : 2.66 (s, 3H), 2.8 - 3.2
(m, 2H), 3.4 - 4.2 (m, 4H),
3.86 (s, 3H), 3.88 (s, 3H),
4.28 (s, 2H), 4.9 - 5.4 (m, 2H),
6.55 (d, lH, J=8.8 Hz),
7.25 (d, lH, J=8.8 Hz)
IR (~Br) cm 1 3420, 2920, 2350, 1620, 1510, 1480,
1420, 1280, 1220, 1100, 1030, 950,
790
Example 19
Methyl 4-(2-hydroxybenzyl)-1-piperazine-
carbodithioate (Com. No. 4)
In 10 ml of ethanol was dissolved 0.86 g of 35 %
formalin. To the solution was dropwise added under chil-
: ling with ice a solution of 2.35 g of methyl 1-pipera-
30 zinecarbodithioate in 4 ml of ethanol. The mixture was
then stirred for 30 min. at room temperature. The mix-
ture was refluxed overnight under heating after addition
of a solution of 2.82 g of phenol in 4 ml of ethanol
- 44 _ l 3 3 7 7 6 8
under chilling with ice and subsequent stirring at room
temperature for 3 hours. The reaction mixture was cooled
to room temperature. A half amount of the solvent was
distilled off under reduced pressure. To the residue was
5 added 5 ml of ether to precipitate crystals. The cry-
stals were collected by filtration and washed with lS ml
of ether to give 1.63 g of crude crystals of the desired
compound. The crude crystals were then dissolved in
chloroform. To the chloroform solution was added ethanol
10 in twice amount of the amount of the chloroform.
Precipitated crystals were collected by filtration to
give 0.95 g of the desired compound as a white
crystalline product, m.p. 147 C, yield 33.4 %.
1H-NMR (CDCQ3)~: 2.5 - 2.8 (m, 4H), 2.66 (s, 3H),
3.73 (s, 2H), 4.2 (br, 4H),
6.7 - 7.3 (m, 4H)
IR (KBr) cm 1 3400, 2820, 1580, 1420, 1270, 1250,
1220, 980, 920, 750
Example 20
i) Methyl 4-(2,3-dihydroxybenzyl)-1-piperazine
carbodithioate (Com. No. 15)
1.10 g of catechol, 2.11 g of methyl 1-piperazine-
carbodithioate, 0.36 g of paraformaldehyde and 10 ml of
chloroform were mixed and refluxed overnight under heat-
25 ing. The heated mixture was then cooled to room tempera-
ture, and impurities were removed. The chloroform por-
tion was washed successively with water and a saturated
aqueous sodium chloride solution, dried over anhydrous
sodium sulfate, and placed under reduced pressure to dis-
30 till off the solvent. The residue was purified by silicagel column chromatography and crystallized from ethanol.
The obtained crystals (1.09 g) were dissolved in 4 ml of
chloform. To the solution was added 8 ml of ethanol.
- _ - 45 -
1 337768
Precipitated crystals were collected by filtration to
give 0.94 g of the desired compound as a white crystal-
line product, yield 34.6 %.
ii) Methyl 4-(2,3-dihydroxybenzyl)-1-piperazine
carbodithioate hydrochloride
In 3 ml of acetone was dissolved 250 mg of methyl
4-(2,3-dihydroxybenzyl)-1-piperazinecarbodithioate. To
the solution was dropwise added under chilling with ice
0.84 ml of 1-N HC~/ether mixture, and the resulting mix-
10 ture was stirred at room temperature. The solvent was
distilled off under reduced pressure. The residue was
stirred at room temperature with 2 ml of acetone. Pre-
cipitated crystals were collected by filtration and
washed with 4 ml of acetone to give 213 mg of the desired
15 compound as a white powder, m.p. 187 - 189C (decomp.),
yiled 76.2 %.
H-NMR (CD30D) ~: 2.65 (s, 3H), 3.1 - 3.6 (br, 6H),
3.8 - 5.1 (m, 2H), 4.40 (s, 2H),
6.6 - 7.0 (m, 3H)
20 IR (KBr) cm : 3460, 3260, 2580, 1600, 1480, 1400,
1280, 1240, 1210, 980, 730
Example 21
i) Methyl 4-(3,5-dimethoxy-4-hydroxybenzyl)-1-
piperazinecarbodithioate (Com. No. 43)
In 10 ml of ethanol was dissolved 0.86 g of 35 %
formaline. To the solution was dropwise added under
chilling with ice a solution of 2.35 g of methyl 1-
piperazinecarbodithioate in 4 ml of ethanol. The result-
ing mixture was then stirred for 30 min. at room tempera-
30 ture. Under chilling with ice, a solution of 1.54 g of
2,6-dimethoxyphenol in 4 ml of ethanol was to the stirred
mixture. The resulting mixture was stirred for one hour
at room temperature, and then refluxed under heating for
~ 46 -
1 337768
38 hours. The refluxed mixture was then cooled to room
temperature. Precipitated crystals were collected by
filtration and then washed with ethanol to give 1.94 g of
the desired compound a whilte crystalline product, yield
5 56.7 %.
H-NMR (CDC~3) ~: 2.3 - 2.7 (m, 4H), 2.66 (s, 3H),
3.45 (s, 2H), 3.87 (s, 6H),
4.1 (s, 4H), 5.59 (s, lH),
6.55 (s, 2H)
ii) Methyl 4-(3,5-dimethoxy-4-hydroxybenzyl)-1-
piperazinecarbodithioate hydrochloride
In 4 ml of chloroform was dissolved 500 mg of methyl
4-(3,5-dimethoxy-4-hydroxybenzyl)-1-piperazinecarbodi-
thioate. To the solution was dropwise added under chil-
lS ling with ice 1.46 ml of 1-N HC~/ether mixture. The
solvent was then distilled off under reduced pressure.
The residue was stirred overnight at room temperature
together with 8 ml of ethyl acetate. Precipitated cry-
stals were collected by filtration to give 529 mg of the
20 desired compound as a white powder, m.p. 187 - 188C
(decomp.), yiled 95.9 %.
H-NMR (CD30D)~ : 2.65 (s, 3H), 2.9 - 4.1 (m, 4H),
3.89 (s, 6H), 4.29 (s, 2H),
4.1 - 4.9 (m, 2H), 4.9 - 5.5
(m, 2H), 6.87 (s, 2H),
IR (KBr) cm : 3400, 3100, 2520, 1610, 1510, 1460,
1420, 1330, 1270, 1240, 1210, 1110,
940
Example 22
Methyl 4-(5-formyl-2-hydroxy-3-methoxybenzyl)-1-
piperazinecarbodithioate (Com. No. 38)
In 10 ml of ethanol was dissolved 0.86 g of 35 %
formalin. To the solution was dropwise added under chil-
_ ~ 47 ~ l 3 3 7 7 6 8
ling with ice a solution of 1.94 g of methyl 1-pipera-
zinecarbodithioate in 4 ml of ethanol. The mixture was
then stirred for 30 min. at room temperature. Under
chilling with ice, a solution of 1.52 g of vanilline in 4
5 ml of ethanol was added to the reaction mixture. The
mixture was stirred for 40 min. at room temperature and
then refluxed under heating for 10 hours. The reaction
mixture was cooled to room temperature to precipitate
crystals. The crystals were collected and washed with
10 ethanol to give 2.58 g of the desired compound as a white
crystalline product, m.p. 144 - 145C (decomp.), yield
75.8 %.
H-NMR (CDCl3) ~ : 2.4 - 2.8 (m, 4H), 2.66 (s, 3H),
3.84 (s, 2H), 3.95 (s, 3H),
3.9 - 4.4 (m, 4H), 7.1 - 7.4
(m, 2H), 9.78 (s, lH)
IR (KBr) cm 1 3350, 2800, 1660, 1590, 1490, 1450,
1420, 1300, 1240, 1190, 1140, 1060,
990, 920, 860, 710
Example 23
i) Methyl 4-(6,7-dihydroxycumarin-8-yl)methyl-
1-piperazinecarbodithioate (Com. No. 106)
To 10 ml of methanol were successively added 0.375
ml of 37 % formalin, 882 mg (5 mmol.) of methyl l-pipera-
25 zinecarbodithionate,891 mg (5 mmol.) of aesculetin (6,7-dioxy-
cumarin) and 5 ml of methanol. The mixture was stirred
for 2.5 hours at room temperature, and then refluxed
under heating and stirring for 18 hours, to undergo a re-
action. The reaction mixture was then cooled to deposit
30 a precipitate. The precipitate was collected by filtra-
tion and washed successively with methanol, ethanol and
n-hexane to give 1.36 g of the desired compound, yield
74.3 %.
- _ - 48 - l 3377 b8
H-NMR (CDCl3) ~ : 2.67 (s, 3H), 2.40 -2.90 (m, 4H),
3.90 - 4.40 (m, 4H), 4.11 (s, 2H),
6.22 (d, lH), 6.92 (s, lH),
7.57 (d, lH), 8.17 (s, 2H)
ii) Methyl 4-(6,7-dihydroxycumarin-8-yl)methyl-
l-piperazinecarbodithioate hydrochloride
The above obtained compound was dissolved in a
mixture of methanol and chloroform. A methanol solution
of hydrogen chloride gas was added to the resulting
10 solution, to yield the desired hydrochloride, m.p. 217 -
220C (decomp.).
H-NMR (CD30D) ~: 2.64 (s, 3H), 3.00 - 3.60 (m, 4H),
4.53 (s, 2H), 4.00 - 4.60 (m, 4H),
6.21 (d, lH), 7.09 (s, lH),
7.83 (d, lH)
IR (KBr) cm 1 3600 - 2300, 1700, 1610, 1570, 1400,
1290, 1260, 1210
Example 24
Methyl-4-{6-(~-D-glucopyranosyloxy)-7-hydroxy-
cumarin-8-yl}methyl-1-piperazinecarbodithioate
(Com. No. 107)
To 10 ml of methanol were successively added 0.375
ml of 37 % formalin, 0.88 g (5 mmol.) of methyl l-pipera-
zinecarbodithioate, 1.84 g (5 mmol.) ofesculetin (~-
25 esculetin -6-~-glucoside) and 5 ml of methanol. The
mixture was stirred refluxed under heating and stirring
for 4 hours, to undergo a reaction. The reaction mixture
was then cooled to deposit a yellow syrup. The syrup was
then separated from methanol by decantation and converted
30 into a powdery deposit by addition of ether. The powdery
deposit was collected by filtration and washed succes-
sively with ether and n-hexane to give 7.7 g of the
desired compound, m.p. approx. 170C (decomp.).
1 337768
1H-NMR tDMSO-d6) ~: 2.56 (s, 3H), 2.40 -2.80
(m, 4H), 3.00 - 4.40 (m, 12H),
4.40 - 5.40 (m, 6H), 6.24 (d, lH)~
7.38 (s, lH), 7.85 (d, lH)
Example 25
Methyl 4-( 6, 7-dihydroxycumarin-8-yl)methyl-1-
piperazinecarbodithioate hydrochloride
To 0.3 g of the product obtained in Example 23-i)
was added 4.5 ml of 10 % hydrochloric acid. The mixture
10 was heated to 100 - 110 C for 80 min. The solvent was
distilled off under reduced pressure. To the residue was
added water. Insolubles were removed by filtration. The
From the filtrate, the same hydrochloride as that of
Example 23-ii) was obtained.
Example 26
i) Methyl 4-{2-(3,4-dihydroxyphenyl)-2-oxo}ethyl-
1-piperazinecarbodithioate (Com. No. 72)
In 2 ml of ethanol was dissolved 184 mg (1.044
mmol.) of methyl 1-piperazinecarbodithioate. To the
20 resulting solution were added 195 mg (1.045 mmol) of 2-
chloro-3',4'-dihydroxyacetophenone and 3 ml of ethanol.
When the introduced solid material was dissolved in the
mixture, 333 mg of sodium carbonate was added to the mix-
ture. The mixture was then stirred for one hour at room
25 temperature and then refluxed under heating and stirring
for 3 hours. Ethanol was distilled off under reduced
pressure, and 5 ml of water and 0.4 g of acetic acid were
added to the residual gum. The gum was extracted with
chloroform. The chloroform extract was dried over anhy-
30 drous sodium sulfate, placed under reduced pressure todistill off chloroform. The syrupy residue (0.3 g) was
- 50 -
1 337768
then crystallized from ethanol, collected by filtration,
and washed successively with ethanol and n-hexane to give
0.13 g of the desired compound as a pale brown powder,
m.p. 184 - 186C (decomp.), yield 42.3 %.
lH-NMR (DMS0-d6)~ : 2.40 - 2.90 (m, 4H), 2.57
(s, 3H), 3.80 (s, 2H),
3.86 - 4.50 (br, s, 4H),
6.79 (d, lH, J=6.8 Hz),
7.10 - 7.50 (m, 2H)
IR (KBr) cm 1 3400, 2900, 1660, 1600, 1500, 1470,
1420, 1380, 1340, 1280, 1250, 1160,
1110
ii) Methyl 4-{2-(3,4-dihydroxyphenyl)-2-oxo}ethyl-
1-piperazinecarbodithioate hydrochloride
The above obtained compound was dissolved in ethan-
ol. A methanol solution of hydrogen chloride gas was
added to the resulting solution. Methanol was distilled
off under reduced pressure. Ether was added to the resi-
due to give a precipitate. The precipitate was collected
20 by filtration, washed with ether and n-hexane, and dried
to yield the desired hydrochloride, m.p. 210C (decomp.).
H-NMR (CD30D)~ : 2.65 (s, 3H), 3.10 - 3.60 (m, 4H),
4.20 - 4.60 (m, 4H), 4.76 (s, 2H),
6.87 (d, lH, J=9 Hz),
7.20 - 7.60 (m, 2H)
IR (KBr) cm 1 3600 - 2300, 1660, 1590, 1510, 1400,
1330, 1280, 1180, 1110, 1010, 960
Example 27
i) Methyl 4-~2-(3,4-dihydroxyphenyl)-2-hydroxy}-
ethyl-1-piperazinecarbodithioate (Com. No. 73)
To 1,025 mg (3.14 mmol.) of methyl 4-{2-(3,4-
dihydroxyphenyl)-2-oxo}ethyl-1-piperazinecarbodithioate
hydrochloride were added 56 ml of ethanol and 15 ml of
- Sl 1 3 3 7 7 6 8
tetrahydrofuran (THF). The mixture was chilled to -10C,
and 1.10 g of sodium borohydride was added to the mixture
for 15 min. The mixture was then stirred at -10 - 0C for
5 hours, and again chilled to -10C. To the chilled
5 mixture was added 1.78 g of acetic acid to decompose
excessive sodium borohydride. The solvent was distilled
off, and water was added to the residue to precipitate a
gum. The gum was then extracted with ethyl acetate. The
organic portion was taken out, washed with a saturated
10 aqueous sodium chloride solution, dried over anhydrous
sodium sulfate, and treated to distill off the solvent,
to yield white crystals. The crystals were washed with
ether, collected by filtration, and washed with n-hexane
to give 0.59 g of the desired compound, yield 57.2 %.
1H-NMR (CD30D)~ : 2.20 - 2.90 (m, 6H), 2.61 (s, 3H),
3.90 - 4.30 (m, 4H),
4.67 (t, lH, J=4 Hz),
6.50 - 6.90 (m, 3H)
IR (KBr) cm : 3600 - 3000, 1590, 1500, 1410, 1270,
1220
ii) Methyl 4-{2-(3,4-dihydroxyphenyl)-2-hydroxy}-
ethyl-1-piperazinecarbodithioate hydrochloride
The above obtained compound was dissolved in methan-
ol. A methanol solution of hydrogen chloride gas was
25 added to the resulting solution. Methanol was distilled
off under reduced pressure. The residue was washed with
ether to yield the desired hydrochloride.
H-NMR (CD30D)~ : 2.64 (s, 3H), 2.70 - 3.40 (m, 6H),
4.10 - 4.50 (m, 4H), 4.60 - 5.00
(m, lH), 6.60 - 6.90 (m, 3H)
IR (KBr) cm : 3600 - 2300, 1600, 1510, 1450, 1400,
- 1270, 1220
- _ - 52 - - l 337768
Example 28
i) a-Bromo-2,3,4-trimethoxyacetophenone
25 g of 2,3,4-trimethoxyacetophenone, 600 ml of
ether and 240 ml of chloroform were mixed. To the
5 resulting mixture was dropwise added under chilling with
ice/sodium chloride mixture a solution of 19.18 g of
bromine in 120 ml of chloroform for 3.3 hours. The
resulting solution was washed successively with chilled
water, chilled 5% aqueous sodium hydroxide solution,
10 chilled water and aqueous sodium chloride solution, and
dried over anhydrous sodium sulfate. Thereafter, the
solvent was distilled off under reduced pressure at a
temperature of lower than 50C, leaving 33.0 g of yellow
oil, yield 91.7 %.
1H-NMR (CDCl3)~ : 3.86 (s, 3H), 3.92 (s, 3H),
4.05 (s, 3H), 4.56 (s, 2H),
6.73 (d, lH, J=9 Hz),
7.60 (d, lH, J=9 Hz)
IR (neat) cm 1 2950, 1680, 1490, 1410, 1290, 1210,
1110, 1000, 810
ii) Methyl 4-{2-(2,3,4-trimethoxyphenyl)-2-oxo}-
ethyl-1-piperazinecarbodithioate (Com. No. 71)
16 g of ~-bromo-2,3,4-trimethoxyacetophenone, 13.25
g of methyl 1-piperazinecarbodithioate, 17.6 g of sodium
25 carbonate and 27.0 ml of ethanol were mixed and refluxed
under heating for 5.5 hours. The hot reaction solution
was filtered to remove the inorganic solid. The inor-
ganic solid was washed with chloroform. The filtrate and
the washing were combined and placed under reduced pres-
30 sure to distill off the solvent. The obtained residuewas extracted with chloroform. The chloroform extract
was washed successively with water and an aqueous sodium
chloride soltuion, and dried over anhydrous sodium sul-
fate. The solvent was distilled off under reduced pres-
- ~ ~ 53 ~ l 337768
sure, leaving 26.5 g of a crystalline product. The cry-
stalline product was recrystallized from 50 ml of ethanol
to give 12.68 g of the desired compound as a pale brown
needle-crystalline product, m.p. 96 - 98C, yield 59.7 %.
lH-NMR (CDC~3)~ : 2.5 - 2.8 (m, 4H), 2.66 (s, 3H),
3.84 (s, 2H), 3.86 (s, 3H),
3.91 (s, 3H), 3.98 (s, 3H),
4.22 (br, 4H),
6.72 (d, lH, J=9 Hz),
7.53 (d, lH, J=9 Hz)
IR (KBr) cm 1 3400, 2900, 2800, 1670, 1590, 1460,
1390, 1290, 1220, 1140, 1090, 1020,
1000, 980, 820
Example 29
i) Methyl 4-{2-(2,3,4-trimethoxyphenyl)ethyl}-
1-piperazinecarbodithioate (Com. No. 67)
In a nitrogen atmosphere, 5 g of methyl 4-{2-(2,3,4-
trimethoxyphenyl)-2-oxo}ethyl-1-piperazinecarbodithioate,
2.4 g of sodium borohydride and 4.7 g of anhydrous alumi-
20 num trichloride were mixed. To the mixture was then
added 120 ml of dry tetrahydrofuran, and the resulting
mixture was stirred for 6 hours. The mixture was chilled
with ice. To the chilled mixture were added 48 ml of
water. The aqueous mixture was extracted with ethyl
25 acetate. The extract was washed with an aqueous sodium
chloride solution, dried over anhydrous sodium sulfate,
and placed under reduced pressure to distill off the
solvent. An inorganic solid in the residue was removed
by filtration. The extract was purified by silica gel
30 column chromatography, to yield 1.18 g of the desired
compound, yield 24.5 %.
H-NMR (CDC3) S: 2.4 - 2.8 (m, 8H), 2.67 (s, 3H),
3.84 (s, 3H), 3.86 (s, 3H),
~ ~ 54 ~ l 337768
3.88 (s, 3H), 4.07 (br, 4H),
6.59 (s, lH, J=8.4 Hz),
6.83 (s, lH, J=8.4 Hz)
IR (neat) cm 1 Z980 - 2825, 1730, 1600, 1490, 1460,
1410, 1270, 1215, 1130, 1095, 1050,
1005, 990, 925, 795
ii) Methyl 4-t2-(2~3~4-trimethoxyphenyl)ethyl}
1-piperazinecarbodithioate hydrochloride
In 2.0 ml of dichloromethane was dissolved 250 mg of
10 the above-obtained product. Under chilling with ice,
0.67 ml of 1-N HC~/ether mixture was added to the result-
ing solution. The solvent was distilled off under
reduced pressure. To the residue was added 1.6 ml of
ethanol, and precipitated crystals were collected by fil-
15 tration. The crystals were washed with 2 ml of ethanol
to give 159 mg of the desired compound as a white powder,
m.p. 202 - 203C, yield 58.2 %.
H-NMR (CD30D)~ : 2.67 (s, 3H), 2.6 - 3.2 (br, 2H),
2.9 - 3.3 (br. 4H), 3.3 - 4.3
(br, 4H), 3.84 (s, 6H), 3.92
(s, 3H), 4.9 - 5.4 (br, 2H),
6.59 (d, lH, J=8.4 Hz),
6.92 (d, lH, J=8.4 Hz)
IR (KBr) cm 1 3450, 2930, 2530, 2360, 1600, 1490,
1470, 1420, 1270, 1240, 1190, 1110,
1050, 960, 910, 800, 620
Example 30
Methyl 4-{2-(2,3,4-trihydroxyphenyl)ethyl}-
1-piperazinecarbodithioate (Com. No. 68)
In 14 ml of dry dichloromethane was dissolved 1 ml
of boron tribromide. 9.3 ml of the resulting solution
containing 665 mmol. of boron tribromide was chilled to
-50C in a nitrogen atmosphere. To the chilled solution
- 55 - l 3 3 7 7 6 8
was dropwise added a solution of 0.73 g of methyl 4-{2-
(2,3,4-trimethoxyphenyl)ethyl}-1-piperazinecarbodithioate
in 25 ml of dry dichloromethane for 15 min. The result-
ing mixture was left to reach room temperature, and then
5 stirred overnight. To the mixture was added 3 ml of
water, and further added a saturated aqueous sodium
hydrogen carbonate solution until the mixture had pH 8.
The mixture was then extracted with ethyl acetate. The
extract was dried over anhydrous sodium sulfate and
10 placed under reduced pressure to distill off the solvent,
yielding 205 mg of the desired compound as a grayish
powder, m.p. 156 - 158C (decomp.), yield 31.5 %.
H-NMR (CD30D)~ : 2.63 (s, 3H), 2.5 - 2.9 (m, 8H),
4.0 - 4.4 (m, 4H)
6.23 (d, lH, J=8.4 Hz),
6.33 (d, lH, J=8.4 Hz)
IR (KBr) cm 1 3400, 2900, 1630, 1460, 1420, 1260,
1220, 1100, 1040, 920, 760, 610
Example 31
i) 1-(3,4,5-Trimethoxyphenyl)piperazine
11.9 g of 3,4,5-trimethoxyaniline, 11.6 g of bis-
(2-chloroethyl)amine hydrochloride, 9 g of anhydrous
potassium carbonate, and 48 ml of diglyme were mixed and
refluxed under heating for 28 hours. The reaction mix-
25 ture was cooled, and was added into 100 ml of water. A
concentrated aqueous potassium hydroxide solution was
added to the aqueous mixture until the mixture had pH 12.
The aqueous solution was then extracted with ethyl acet-
ate. The ethyl acetate portion was washed with water,
30 dried over anhydrous sodium sulfate, and placed under
reduced pressure to distill off the solvent. The residue
was purified by silica gel column chromatography to give
2.37 g of the desired compound as a brown oil.
_ - 56 - l 337768
H-NMR (CDC3) ~: 1.72 (s, lH), 3.06 (s, 8H),
3.78 (s, 3H), 3.84 (s, 6H),
6.12 (s, 2H)
ii) 4-(3,4,5-Trimethoxyphenyl)-1-piperazinecarbo-
dithioic acid (Com. No. 94)
In a nitrogen atmosphere, 1.9 g of 1-(3,4,5-tri-
methoxyphenyl)piperazine was dissolved in 10 ml of
methanol. To the solution was dropwise added under chil-
ling with ice 0.46 ml of carbon disulfide. After the
10 addition was complete, the mixture was stirred at room
temperature for 2 hours. Precipitated crystals were col-
lected by filtration to give 1.9 g of the desired com-
pound as a gray-brown powder, m.p. 183 - 190C (decomp.),
yield 77.7 %.
1H-NMR (DMS0-d6)~ : 2.9 - 3.4 (m, 7H), 3.57 (s, 3H),
3.75 (s, 6H), 4.4 (br, 2H),
6.21 (d, 2H, J=3.3 Hz),
IR (KBr) cm : 2930, 2820, 1580, 1510, 1450, 1420,
1240, 1210, 1120, 1000, 930
Example 32
Methyl 4-(3,4,5-trimethoxyphenyl)-1-piperazine-
carbodithioate (Com. No. 70)
In a nitrogen atmosphere, 1.5 g (4.6 mmol.) of 4-
(3,4,5-trimethoxyphenyl)-1-piperazinecarbodithioic acid
25 was suspended in methanol. After addition of 0.2 g of
granular sodium hydroxide, the suspension was stirred at
room temperature for one hour. The reaction mixture was
chilled in a mixture of ice and sodium chloride. To the
reaction mixture was dropwise added a solution of 0.29 ml
30 of methyl iodide in 3.7 ml of methanol. After the addi-
- tion was complete, the mixture was stirred at room tem-
perature for 1 hour. Precipitated crystals were col-
lected by filtration to give 0.8 g of the desired com-
1 337768
- 57 -
pound as a gray-brown powder, m.p. 135 - 137C (decomp.),
yield 50.8 Y0.
H-NMR (CDC~3)~ : 2.69 (s, 3H), 3.1 - 3.3 (m, 4H),
3.79 (s, 3H), 3.85 (s, 6H),
4.31 (br, 4H), 6.16 (s, 2H)
IR (KBr) cm 1 1580, 1510, 1460, 1420, 1270, 1220,
1110, 980, 930, 820, 760
Example 33
Methyl 4-(1,4-benzoquinonylmethyl)-1-piperazine-
carbodithioate (Com. No. 110)
In a mixture of 6.8 ml of l-N hydrochloric acid and
6.8 ml of methanol was dissolved 680 mg of methyl 4-(2,5-
dihydroxybenzyl)-l-piperazinecarbodithioate. The result-
ing solution was chilled with ice, and to this was drow-
15 pise added a solution of 1.24 g (5.3 mmol.) of Fe~Q3-6H20
in 4.3 ml of water for 15 min. To this was further added
25 ml of methanol. To thus obtained homogeneous solution
was again added a solution of 2.2 g of FeC3-6H20 in 10
ml of water. The mixture was then stirred for 10 min.
20 and placed under reduced pressure to distill off methan-
ol. To the residue was added 50 ml of chloroform, and to
this was added a saturated sodium hydrogen carbonate to
adjust pH of the mixture to 7. Insolubles were removed
by filtration. The organic solvent portion was taken
25 out, washed with water and a saturated aqueous sodium
chloride solution, dried over anhydrous sodium sulfate,
and placed under reduced pressure to distill off the
solvent. The residue was then purified by silica gel
column chromatography to give 234 m8 of the desired com-
30 pound as a yellow powder, m.p. 115 - 116C (decomp.),
yield 38.9 %.
H-NMR (CDC~3)~ : 2.3 - 2.8 (m, 4H), 2.66 (s, 3H),
3.40 (d, 2H, J=2 Hz), 3.9 - 4.4
- ~ - 58 - - l 33776~
(m, 4H), 6.6 - 6.9 (m, 3H)
IR (KBr) cm 1 3420, 1650, 1465, 1420, 1290, 1230,
995, 910
Example 34
i) Methyl 4-[(2,5-dihydroxy-3,4,6-trimethyl)-
benzyl]-1-piperazinecarbodithioate (Com. No. 46)
In 30 ml of ethanol was dissolved 2.58 g (30 mmol.)
of 35 % formalin. Under chilling with ice, to the solu-
tion was dropwise added a solution of 5.88 g (30 mmol.,
10 purity 90 %) of methyl 1-piperazinecarbodithioate in 15
ml of ethanol. The mixture was then stirred for 30 min.
at room temperature. To the mixture was dropwise added
under chilling with ice a solution of 4.57 g (30 mmol.)
of 2,3,5-trimethylhydroquinone in 30 ml of ethanol. The
15 mixture was stirred at room temperature for 30 min. The
mixture was refluxed under heating for approx. 35 hours
and subsequently treated to distill off the solvent. To
the residue was added ether. Thus obtained precipitate
was collected by filtration to give 3.13 g of the desired
20 compound as a pale brown powder, yield 30.6 %.
H-Nr~R (CDCl3) ~: 2.15 (s, 9H), 2.40 - 2.7 (m, 7H),
3.70 (s, 2H), 3.9 - 4.4 (m, 4H)
ii) Methyl 4-t(2,5-dihydroxy-3,4,6-trimethyl)-
benzyl]-1-piperazinecarbodithioate hydrochloride
In 10 ml of chloroform was dissolved 0.5 g (6.47
mmol.) of the above-obtained product. Under chilling
with ice, 1.47 ml of 1-N HCl/ether mixture was added to
the resulting solution. The solvent was distilled off
under reduced pressure. To the residue was added 6 ml of
30 acetone, and precipitated crystals were collected by fil-
tration to give 0.35 g of the desired compound as a white
powder, m.p. 166 - 169C (decomp.), yield 70.0 %.
1H-NMR (CD30D/CDCl3=3/1)~ :
_ - 59 _ l 33/ ~68
2.20 (s, 6H), 2.30 (s, 3H), 2.67
(s, 3H), 3.1 - 3.6 (br, 4H),
3.6 - 4.1 (br, 2H), 4.46 (s, 2H),
4.8 - 5.3 (br, 2H)
IR (KBr) cm 1 3300, 2900, 2600, 1700, 1605, 1455,
1400, 1250, 1210, 1190, 1110, 1075,
1020, 930
Example 35
Methyl 4-(3,5,6-trimethyl-1,4-benzoquinonylmethyl)-
1-piperazinecarbodithioate (Com. No. 113)
In a mixture of 10 ml of 1-N hydrochloric acid and
16 ml of methanol was dissolved 1,020 mg (3 mmol.) of
methyl 4-[(2,5-dihydroxy-3,4,6-trimethyl)benzyl]-1-
piperazinecarbodithioate. The resulting solution was
15 chilled with ice, and to this was drowpise added a solu-
tion of 1.86 g (7.95 mmol.) of FeC~3 6H20 in 6.4 ml of
water for 5 min. To this was further added a solution of
1.86 g (7.95 mmol.) of FeCl3 6H20 in 6.4 ml of water.
The mixture was stirred and then treated to distill off
20 methanol. To the residue was added 75 ml of chloroform
and further added an aqueous sodium hydrogen carbonate,
until the mixture was neutralized. A precipitated red-
brown solid was removed by filtration, and the organic
portion was taken out. The organic portion was washed
25 with water and a saturated sodium chloride solution,
dried over anhydrous sodium sulfate, and placed under
reduced pressure to distill off the solvent. The residue
was crystallized from ethanol, and the crystals were
collected by filtration to give 840 mg of the desired
30 compound as an orange powder, m.p. 133 - 135C.
H-NMR (CDC~3)~ : 2.03 (s, 6H), 2.13 (s, 3H), 2.4 -
2.6 (m, 4H), 2.65 (s, 3H), 3.45
(s, 2H), 3.9 - 4.2 (m, 4H)
- 60 -
1 337768
IR (KBr) cm : 3400, 2900, 2790, 1630,
1620 (shoulder), 1460, 1420, 1365,
1280, 1255, 1220, 1135, 1020, 990,
950, 915
Example 36
i) 3,4-Dimethoxybenzyl chloride
In a nitrogen atmosphere, 5 g (29.73 mmol.) of 3,4-
dimethoxybenzyl alcohol was dissolved in 25 ml of di-
chloromethane. The obtained solution was placed in an
10 ice-bath, and to this was dropwise added a solution of
2.16 ml (29.74 mmol.) of thionyl chloride in 5 ml of
methylene chloride. The mixture was then stirred at room
temperature for 1 hour. The mixture was placed under
reduced pressure at room temperature to distill off the
15 solvent to give 5.624 g of the desired compound as a
yellow oil.
H-NMR (CDC~3) ~: 3.86 (s, 3H), 3.88 (s, 3H),
4.57 (s, 2H), 6.7 - 7.0 (m, 3H)
ii) Methyl 4-(3,4-dimethoxybenzyl)-1-piperazine-
carbodithioate (Com. No. 31)
In a nitrogen atmosphere, 5.615 g (30.08 mmol.) of
3,4-dimethoxybenzyl chloride, 5.57 g (30.08 mmol., purity
95 ,') of methyl 1-piperazinecarbodithioate, 3.19 g (30.08
mmol.) of anhydrous sodium carbonate and 50 ml of ethanol
25 were mixed and refluxed under heating for 5.5 hours. The
solvent was distilled off under reduced pressure. To the
residue were added 20 ml of dichloromethane and 20 ml of
water. The organic solvent portion was taken out and
washed with 30 ml of 1-N hydrochloric acid. To the
30 organic portion was added 1-N aqueous sodium hydroxide
solution. The organic solvent portion was again taken
out and dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure. To the residue
- 61 _ ~ 3 3 7 7 6 8
was added 20 ml of ethanol. Precipitated crystals were
collected by filtration and washed with ethanol to give
1.465 g of methyl 4-(3,4-dimethoxybenzyl)-1-piperazine-
carbodithioate, yield 14.9 %.
iii) Methyl 4-(3,4-dimethoxybenzyl)-1-piperazine-
carbodithioate hydrochloride
In 2.5 ml of ethanol was suspended 1 g (3.06 mmol.)
of the above-obtained crystals. To the suspension was
dropwise added under chilling with ice 0.51 g of 6-N HCI
10 in ethanol. The solvent was distilled off under reduced
pressure, and 3 ml of ethanol was added to the residue.
Precipitated crystals were collected by filtration to
give 0.866 g of the desired compound as a white powder,
m.p. 138 - 140C (decomp.), yield 78.1 %.
1H-NMR (CDCl3)~ : 2.65 (s, 3H), 2.6 - 3.1 (m, 2H),
3.2 - 3.7 (m, 2H), 3.89 (s, 3H),
3.97 (s, 3H), 3.9 - 4.3 (m, 4H),
4.9 - 5.5 (m, 2H), 6.6 - 7.1
(m, 2H), 7.3 - 7.6 (m, lH)
IR (KBr) cm 1 2920, 2520, 2440, 1630, 1590, 1520,
1460, 1410, 1265, 1240, 1220, 1160,
1140, 1110, 1020, 950
Example 37
Methyl 4-(2-dimethylaminobenzyl)-1-
piperazinecarbodithioate (Com. No. 13)
In 20 ml of acetone, 2.06 g (10 mmol.) of 2-di-
methylaminobenzyl chloride hydrochloride, 1.76 g (10
mmol.) of methyl piperazinecarbodithioate, and 1.06 g (10
mmol.) of sodium carbonate were stirred overnight at room
30 temperature. Acetone was distilled off under reduced
pressure. Water was added to the residue. The aqueous
mixture was extracted with ether. The ether portion was
washed with water and a saturated aqueous sodium chloride
- 62 - 1337768
solution, dried over anhydrous sodium sulfate, and placed
under reduced pressure to distill off the solvent. The
residue was purified by means of silica gel column and
then recrystallized from ether to give 1.32 g of the
5 desired compound as a white crystalline product, m.p. 90
- 91C, yield 42.7 %.
H-NMR (CDC~3)~ : 2.4 - 2.8 (m, 4H), 2.64 (s, 3H),
2.68 (s, 6H), 3.62 (s, 2H), 3.8 -
4.4 (m, 4H), 6.8 - 7.5 (m, 4H)
10 IR (KBr) cm : 2820, 1450, 1425, 1265, 1230, 1185,
1135, 1125, 1040, 990, 940, 760, 720
Example 38
i) 2,3-Dimethoxybenzyl chloride
In 30 ml of methylene chloride was dissolved 3.36 g
15 (20 mmol.) of 2,3-dimethoxybenzyl alcohol. Under chil-
ling with ice, to the solution was dropwise added a solu-
tion of 1.5 ml (22 mmol.) of thionyl chloride in 5 ml of
methylene chloride for 10 min. The mixture was stirred
at the same temperature and then placed under reduced
20 pressure to distill off the solvent, to give 3.71 g of
2,3-dimethoxybenzyl chloride as a brown oil, yield 99.5
o~o .
ii) Methyl 4-(2,3-dimethoxybenzyl)-1-
piperazinecarbodithioate (Com. No. 22)
To 20 ml of ethanol were added 1.0 g (5.36 mmol) of
2,3-dimethoxybenzyl chloride, 943 mg (5.36 mmol.) of
methyl 1-piperazinecarbodithioate and 568 mg (5.36 mmol.)
of sodium carbonate. The o~tained mixture was refluxed
under heating for 2 hours. Ethanol was distilled off
- 30 under reduced pressure. To the residue was added water.
The aqueous mixture was extracted with 30 ml of ether.
The ether portion was shaken together with 5 ml of 3-N
- 63 -
1 337768
hydrochloric acid. An oil which was insoluble in either
portion and the aqueous portion were combined. The com-
bined mixture was extracted with ether, after addition of
20 ml of 1-N aqueous sodium hydroxide solution. The
5 ether extract was washed with water and a saturated
aqueous sodium chloride solution, dried over anhydrous
sodium sulfate, and placed under reduced pressure to
distill off the solvent. The residue was recrystallized
from ethanol to give 708 mg of the desired compound, m.p.
10 110 -111C, yield 40.5 %.
H-NMR (CDC~3)~ : 2.4 - 2.7 (m, 4H), 2.64 (s, 3H),
3.59 (s, 2H), 3.82 & 3.86
(each s, 6H), 3.9 - 4.4 (m, 4H),
6.7 - 7.1 (m, 3H)
IR (KBr) cm 1 1480, 1425, 1255, 1225, 1135, 1065,
1005, 995, 780
Example 39
Methyl 4-(2,5-dihydroxy-3,4-dimethoxy-6-methyl-
benzyl)-1-piperazinecarbodithioate (Com. No. 47)
In 28 ml of ethanol was dissolved 1.82 g (10 mmol.)
of 2,3-dimethoxy-5-methyl-1,4-benzoquinone. To the solu-
tion was portionwise added at room temperature 240 mg
(6.3 mmol.) of sodium borohydride. The mixture was stir-
red for 15 min. The mixture was then made acidic by
25 addition of 3-N hydrochloric acid. To the mixture were
added 50 ml of water and 100 ml of ether for performing
extraction. The ether portion was washed with water and
a saturated aqueous sodium chloride solution, dried over
anhydrous sodium sulfate, and placed under reduced pres-
30 sure to distill off the solvent to give 1.72 g of 2,3-
dimethoxy-5-methylhydroquinone as a yellow oil, yield
93.5 %. To the resulting oil were added 1.65 g (9.3
mmol.) of methyl 1-piperazinecarbodithioate and 280 mg
- 64 - l 3 3 7 7 6 8
(9.3 mmol.) of paraformaldehyde. The mixture was added
to 17 ml of chloroform, and the resulting mixture was
refluxed under heating for 6 hours. To the heated mix-
ture was added water. The aqueous mixture was then
5 extracted with chloroform. The chloroform extract was
washed with water and a saturated aqueous sodium chloride
solution, dried over anhydrous sodium sulfate, and placed
under reduced pressure to distill off the solvent. The
residue was dissolved in 10 ml of ethanol. Insolubles
10 were removed by filtration. The filtrate was placed
under reduced pressure to distill off ethanol. The
residue was then purified by means of silica gel column,
to give 1.1 g of a pale yellow oil, yield 31.8 %. The
oil was crystallized from ethanol. The crystals were
15 collected by filtration to give 790 mg of the desired
compound as a yellow crystalline proudct, m.p. 135 -
136Ci
H-NMR (CDC~3)~ : 2.11 (s, 3H), 2.66 (s, 3H), 2.5 -
2.8 (m, 4H), 3.72 (s, 2H),
3.9 & 3.95 (each s, 6H),
4.0 - 4.4 (m, 4H)
IR (KBr) cm 1 3450, 2950, 1465, 1420, 1380, 1270,
1230, 1190, 1120, 1090, 1055, 1050,
985, 965, 920
Example 40
~ethyl 4-(5,6-dimethoxy-3-methyl-1,4-benzoquinonyl-
methyl)-1-piperazinecarbodithioate (Com. No. 118)
To 700 mg (1.88 mmol.) of methyl 4-(2,5-dihydroxy-
3,4-dimethoxy-6-methylbenzyl)-1-piperazinecarbodithioate
30 were added 7 ml of 1-N hydrochloric acid and 17 ml of
methanol. The mixture was chilled with ice, and to the
mixture was dropwise added a solution of 1.76 g (7.52
mmol.) of FeC~3-6H20 in 5 ml of water. The resulting
~ - 65 - 1337768
homogeneous red-colored solution was stirred for 30 min.
and placed under reduced pressure at a temperature of
lower than 50C to distill off methanol. To the residue
was added 50 ml of ethyl acetate, and futher added por-
5 tionwise a saturated aqueous sodium hydrogen carbonatesolution to ad~ust the solution to pH 10. A precipitated
brownish red solid was removed by filtration. Thus
obtained organic filtrate was washed with water and a
saturated aqueous sodium chloride solution, dried over
10 anhydrous sodium sulfate, and placed under reduced pres-
sure to distill off the solvent. The residue was cry-
stallized from ethanol, and collected by filtration, to
give 540 mg of the desired compound as an orange-brown
crystalline powder,-m.p. 115 - 116 C, yield 77.6 %.
1H-NMR (CDC~3)~ : 2.11 (s, 3H), 2.4 - 2.8 (m, 4H),
2.64 (s, 3H), 3.42 (s, 2H),
3.8 - 4.3 (m,-4H), 4.00 (s, 6H)
IR (KBr) cm : 1670, 1640, 1615, 1410, 1260, 1230,
1195, 1150, 990
Example 41
i) rIethyl 4-[(4,6-dimethoxy-2-hydroxy)benzyl]-
-1-piperazinecarbodithioate (Com. No. 37)
In 10 ml of ethanol was dissolved 0.86 g (10 mmol.)
of 35 % formaline. Under chilling with ice, to the solu-
25 tion was dropwise added a solution of 2.35 g (10 mmol.,purity 75 %) of methyl 1-piperazinecarbodithioate in 5 ml
of ethanol. The mixture was stirred at room temperature
for 30 min. To the mixture was then dropwise added under
chilling with ice a solution of 1.54 g (10 mmol.) of 3,5-
30 dimethoxyphenol in 5 ml of ethanol. The resulting sus-
pension was then stirred at room temperature for 30 min.
The suspension was refluxed under heating for 30 min.,
and allowed to cool spontaneously. Precipitated crystals
- 66 - I 3 3 7 7 6 8
were collected by fiItration, washed with 20 ml of ethan-
ol, and dried under reduced pressure, to give 1.345 g of
a crude product. The mother liquer was concentrated, and
the resulting residue was crystallized from 10 ml of
5 ethanol. The crystals were washed and dried to give 1.26
g of second crystals, yield 76.1 %.
H-NMR (CDC3) ~: 2.66 (s, 3H), 2.4 - 2.8 (m, 4H),
3.73 (s, 3H), 3.76 (s, 5H), 3.9 -
4.4 (m, 4H), 5.9 - 6.1 (m, 2H)
ii) Methyl 4-[(4,6-dimethoxy-2-hydroxy)benzyl]-
-1-piperazinecarbodithioate hydrochloride
In 2 ml of chloroform was dissolved 0.50 g (1.46
mmol.) of the above-obtained product. To the solution
was added 1.46 ml of 1-N HC~ in ether. The mixture was
15 placed under reduced pressure to distill off the solvent.
The residue was crystallized from 8 ml of acetone and
collected by filtration, to give 0.48 g of the desired
compound as a white crystalline product, m.p. 153 - 154C
(decomp.), yield 86.8 %.
1H-NMR (CDC~3)~ : 2.65 (s, 3H), 3.0 - 3.6 (m, 6H),
3.78 (s, 3H), 3.87 (s, 3H),
4.34 (s, 2H), 4.4 - 5.2 (m, 2H),
6.16 (s, 2H)
IR (KBr) cm 1 8070, 2930, 2560, 1620, 1590, 1510,
1460, 1420, 1270, 1220, 1200, 1150,
1120, 1100, 940, 820
Example 42
i) 2-Methoxybenzyl chloride
In a nitrogen atmosphere, 2.00 g (14.5 mmol.) of 2-
30 methoxybenzyl alcohol was dissolved in 10 ml of dichloro-
methane. The obtained solution was placed in an ice-
bath, and to this was dropwise added a solution of 1.06
ml (14.6 mmol.) of thionyl chloride in 2 ml of dichloromethane.
_ - 67 - l 337768
The mixture was then stirred at room tempera-
ture for 1.5 hours. The mixture was placed under reduced
pressure at room temperature to distill off the solvent
to give 2.32 g of the desired compound as a yellow oil.
lH-NMR (CDC~3) ~ : 3.87 (s, 3H), 4.64 (s, 2H),
6.7 - 7.4 (m, 4H)
ii) Methyl 4-(2-methoxybenzyl)-1-piperazine-
carbodithioate (Com. No. 5)
In a nitrogen atmosphere, 2.28 g (14.5 mmol.) of 2-
10 methoxybenzyl chloride, 2.69 g (14.5 mmol., purity 94.8
%) of methyl l-piperazinecarbodithioate, 1.53 g (14.5
mmol.) of anhydrous sodium carbonate and 15 ml of ethanol
were mixed and refluxed under heating for 18 hours.
Insolubles were removed by filtration, and the solvent of
15 the filtrate was distilled off under reduced pressure.
To the residue were added 15 ml of dichloromethane and 15
ml of water. The organic solvent portion was taken out,
washed with 17 ml of l-N hydrochloric acid and 20 ml of
l-N aqueous sodium hydroxide solution, and dried over
20 anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure. The residue was purified by
column chromatography to give 1.92 g of methyl 4-(2-
methoxybenzyl)-l-piperazinecarbodithioate, yield 44.7 %.
iii) Methyl 4-(2-methoxybenzyl)-1-piperazine-
carbodithioate hydrochloride
In 5.5 ml of ethanol was suspended 0.87 g (2.95
mmol.) of the above-obtained crystals. To the suspension
was dropwise added under chilling with ice 0.5 ml of 6-N
HC~ in ethanol. The solvent was distilled off under
30 reduced pressure, and 3 ml of ether was added to the
residue. Precipitated crystals were collected by filtra-
tion and washed with 5 ml of ether to give 0.81 g of the
desired compound as a white powder, m.p. 216 - 217C
(decomp.), yield 82.0 %.
lH-NMR (CD30D) ~ : 2.65 (s, 3H), 3.2 - 4.0 (m, 6H),
- 68 -
1 337768
3.94 (s, 3H), 4.42 (s, 2H), 4.8 -
5.4 (m, 2H), 6.9 - 7.6 (m, 4H)
IR (KBr) cm 1 2920, 2510, 2450, 1605, 1495, 1460,
1410, 1250, 1210, 1110, 1040, 1020,
950, 760
Example 43
i) 2,5-Dimethoxybenzyl chloride
In a nitrogen atmosphere, 2.00 g (11.9 mmol.) of
2,5-dimethoxybenzyl alcohol was dissolved in 10 ml of di-
10 chloromethane. The obtained solution was placed in an
ice-bath, and to this was dropwise added a solution of
0.87 ml (12.0 mmol.) of thionyl chloride in 2 ml of
dichloromethane. - The mixture was then stirred at room
temperature for 1.5 hour. The mixture was placed under
15 reduced pressure at room temperature to distill off the
solvent to give 2.22 g of the desired compound as a pale
yellow oil.
H-Nr~R (CDCQ3) ~: 3.76 (s, 3H), 3.81 (s, 3H),
4.59 (s, 2H), 6.7 - 7.0 (m, 3H)
ii) Methyl 4-(2,5-dimethoxybenzyl)-1-piperazine-
carbodithioate (Com. No. 23)
In a nitrogen atmosphere, 2.20 g (11.8 mmol.) of
2,5-dimethoxybenzyl chloride, 2.19 g (11.8 mmol.) of
methyl 1-piperazinecarbodithioate, 1.25 g (11.8 mmol.) of
25 anhydrous sodium carbonate and 15 ml of ethanol were
mixed and refluxed under heating for 18 hours. Insolu-
bles were removed by filtration. The solvent of the
filtrate was distilled off under reduced pressure. To
the residue were added 15 ml of dichloromethane and 15 ml
30 of water. The organic solvent portion was taken out,
washed with 15 ml of 1-N hydrochloric acid and 18 ml of
1-N aqueous sodium hydroxide solution, and dried over
anhydrous sodium sulfate. The solvent was then distilled
_ - 69 - ~ 33~1 6~
off under reduced pressure. The residue was purified by
column chromatography to give 1.23 g of methyl 4-(2,5-
dimethoxybenzyl)-1-piperazinecarbodithioate, yield 31.9
%-
iii) Methyl 4-(2,5-dimethoxybenzyl)-1-piperazine-
carbodithioate hydrochloride
In 5 ml of ethanol was suspended 0.76 g (2.31 mmol.)
of the above-obtained crystals. To the suspension was
dropwise added under chilling with ice 0.4 ml of 6-N HC~
10 in ethanol. The solvent was distilled off under reduced
pressure, and 3 ml of ether was added to the residue.
Precipitated crystals were collected by filtration and
washed with 5 ml of ether to give 0.53 g of the desired
compound as a white powder, m.p. 195 - 197C (decomp.),
15 yield 62.8 %.
H-NMR (CD30D) ~: 2.66 (s, 3H), 3.2 - 3.7 (m, 6H),
- 3.79 (s, 3H), 3.89 (s, 3H),
4.39 (s, 2H), 4.9 - 5.4 (m, 2H),
7.0 - 7.1 (m, 3H)
20 IR (KBr) cm : 2990, 2950, 2830, 2500, 2360, 1500,
1470, 1405, 1280, 1260, 1225, 1045,
1020, 960, 805
Example 44
i) Methyl 4-diphenylmethyl-1-piperazinecarbodi-
thioate (Com. No. 102)
In 25 ml of methanol was dissolved 5.00 g (19.8
mmol.) of 1-benzhydrylpiperazine. To the solution was
dropwise added under chilling with ice a solutin of 1.51
g (19.8 mmol.) of carbon disulfide in 5 ml of methanol.
30 The mixture was then stirred for 30 min. Under chilling
with ice, to-the stirred mixture was added a solution of
3.80 g (19.8 mmol.) of 28 %-sodium methylate-in-methanol
solution. The mixture was then stirred until the mixture
~ 3377 6~
- 70 -
gave a clear solution. To this was added a solution of
2.90 g (19.8 mmol.) of 97 %-iodomethane in 5 ml of
methanol. The mixture was then stirred at room tempera-
ture for 1.5 hours. Precipitated crystals were collected
5 by filtration and washed with methanol, to give 5.78 g of
methyl 4-diphenylmethyl-1-piperazinecarbodithioate.
ii) Methyl 4-diphenylmethyl-1-piperazinecarbodi-
thioate hydrochloride
In 1.4 ml of chloroform was dissolved 0.70 g (2.04
10 mmol.) of the above-obtained crystals. Under chilling
with ice, to the solution were added 2.1 ml of l-N HC~/ether
solution and 2 ml of chloroform. The mixture was stirred
at room temperature for 1 hours. Precipitated crystals
were collected by filtration and washed with chloroform/
15 ether (1/1), to give 0.71 g of the desired compound as a
white powder, m.p. 216 - 218C (decomp.), yield 91.7 %.
H-NMR (CD30D) ~: 2.64 (s, 3H), 3.2 - 3.6 (rn, 4H),
3.8 - 5.2 (m, 4H), 5.46 (s, lH),
7.3 - 7.9 (m, 10 H)
IR (KBr) cm : 2410, 1620, 1470, 1450, 1410, 1275,
1225, 1205, 1120, 1020, 1000, 940,
920, 750, 700
Example 45
i) Methyl 4-(2-methylthiobenzyl)-1-piperazine-
carbodithioate (Com. No. 9)
In 20 ml of ethanol, 2.1 g (12.2 mmol.) of 2-methyl-
thiobenzyl chloride, 2.17 g (12.3 mmol.) of methyl 1-
piperazinecarbodithioate and 1.30 g (12.3 mmol.) of
: sodium carbonate were refluxed under heating for 2 hours.
30 Ethanol was distilled off under reduced pressure. The
residue was extracted with ether, after addition of
water. The ether portion was washed with water and a
saturated aqueous sodium chloride solution, dried over
1 33776~
anhydrous sodium sulfate, and placed under reduced pres-
sure to distill off the solvent. The residue was puri-
fied over silica gel column, to give 1.18 g of the
desired compound as a yellow oil, yield 31 %.
1H-NMR (CDCl3)~: 2.44 (s, 3H), 2.4 - 2.7 (m, 4H),
2.64 (s, 3H), 3.58 (s, 2H), 3.8 -
4.4 (m, 4H), 6.9 - 7.5 (m, 4H)
ii) Methyl 4-(2-methylthiobenzyl)-1-piperazine-
carbodithioate hydrochloride
To 11 ml of methylene chloride was added the above-
obtained oil. To the mixture was added 2 ml of 6-N
HCI in ethanol. The solvent was distilled off under
reduced pressure, and 10 ml of ethyl acetate was added tothe
residue. Precipitated crystals were collected by
15 filtration to give 910 mg of the desired compound as a
white crystalline powder, m.p. 204 - 208C (decomp.),
yield 74 %.
H-NMR (CDC~3/CD30D- 1/4, v/v)~
2.55 (s, 3H), 2.66 (s, 3H), 3.2 -
3.7 (m, 4H), 3.7 - 4.2 (m, 2H),
4.56 (s, 2H), 4.8 - 5.4 (m, 2H),
7.2 - 7.8 (m, 4H)
IR (KBr) cm 1 2350, 1460, 1420, 1270, 1215, 1110,
1035, 1010, 955, 765
Example 46
Methyl 4-(2,3,4-trimethoxyphenylacetyl)-1-
piperazinecarbodithioate (Com. No. 75)
In 6.2 ml of methylene chloride were dissolved 310
mg (1.37 mmol.) of 2,3,4-trimethoxyphenylacetic acid and
30 289 mg (1.64 mmol.) ofmethyl l-piperA7;n~cArhodithioate. To
the solutlon was added 395 mg (1.92 mmol.) of dicyclo-
hexylcarbodiimide. The mixture was stirred at room tem-
perature for 1 hour. A precipitated solid was removed by
~ - 72 - l 3 3 7 7 6 8
filtration, and to the filtrate were added methylene
chloride and 1-N hydrochloric acid. The organic solvent
poriton was taken out, washed with a saturated aqueous
sodium chloride solution, dried over anhydrous sodium
5 sulfate, and placed under reduced pressure to distill off
the solvent. The residue was purified over a silica gel
column. The obtained oil was crystallized from a mixture
of ethanol and hexane, yielding 257 mg of the desired
compound as a white crystalline product, m.p. 119 -
10 120C, yield 48.8 %.
H-NMR (CDC~3)~ : 2.65 (s, 3H), 3.66 (s, 2H), 3.3 -
4.3 (m, 8H), 3.8 - 3.9 (m, 9H),
6.58 & 6.88 (each d, 2H, J=9 Hz)
IR (KBr) cm : 1630, 1490, 1460, 1420, 1275, 1240,
1215, 1090, 1045, 1010, 950
Example 47
i) Methyl 4-(2-nitrobenzyl)-1-piperazinecarbodi-
thioate (Com. No. 10)
To 30 ml of ethanol were added 3.43 g (20 mmol.) of
20 2-nitrobenzyl chloride, 3.52 g (20 mmol.) of methyl 1-
piperazinecarbodithioate, and 2.12 g (20 mmol.) of sodium
carbonate. The mixture was then stirred for 4 hours at
room temperature and futher stirred overnight at 50 -
60C. Ethanol was distilled off under reduced pressure,
25 and the residue was extracted using water and chloroform.
The organic solvent portion was washed with water and a
saturated aqueous sodium chloride solution, dried over
anhydrous sodium sulfate, and placed under reduced pres-
sure to distill off the solvent. The residue was cry-
30 stallized from 40 ml of ether, collected by filtrationand washed with ether, to give 4.3 g of the desired
compound, as a yellow crystalline product, yield 69.1 %.
1H-NMR (CDC~3) ~: 2.52 (t, 4H, J=5 Hz),
~ - 73 -
1 337768
2.64 (s, 3H), 3.83 (s, 2H), 3.9 -
4.4 (m, 4H), 7.2 - 7.9 (m, 4H)
ii) Methyl 4-(2-nitrobenzyl)-1-piperazine-
carbodithioate hydrochloride
s In 2 ml of methylene chloride was dissolved 500 mg
(1.61 mmol.) of the above-obtained crystalline product.
To the mixture was added 2 ml of 6-N HC~ in ethanol. The
solvent was distilled off under reduced pressure. 2 mlof
ethyl acetatewas added to the residue to precipitate cry-
10 stals. The crystals were collected by filtration to give
497 mg of the desired compound as a white crystalline
product, m.p. 208 - 211C (decomp.), yield 88.8 %.
H-Nr~R (DMS0-d6) ~ : 2.61 (s, 3H), 3.0 - 3.5 (m, 4H),
3.7 - 4.9 (m, 4H), 4.59 (s, 3H),
7.5 - 8.2 (m, 4H)
IR (KBr) cm 1 2320, 1520, 1460, 1400, 1335, 1270,
1195, 945
Example 48
Methyl 4-(2-aminobenzyl)-1-piperazinecarbodithioate
20(Com. No. 11)
To a mixture of 4 ml of conc. hydrochloric acid and
4 ml of ethanol was added 622 mg (2.0 mmol.) of methyl 4-
(2-nitrobenzyl)-1-piperazinecarbodithioate. The mixture
was chilled with ice, and then to this chilled mixture
25 was dropwise added under stirring a solution of 2.7 g (12
mmol.) of SnC~2-2H20 in 5 ml of ethanol for 15 min.
After the addition was complete, the mixture was further
stirred at room temperature for 2 hours. Ethanol was
distilled off under reduced pressure, and to the residue
30 were added 10 ml of water and 10 ml of ethyl acetate.
The resulting mixture was made alkaline by addition of
saturated aqueous sodium hydrogen carbonate solution.
Precipitated insolubles were removed by filtration. The
- 74 -
1 337768
organic filtrate was washed with a saturated aqueous
sodium chloride solution, dried over anhydrous sodium
sulfate, and placed under reduced pressure to distill off
the solvent. The residue was crystallized from ether,
5 and collected by filtration, yielding 436 mg of the
desired compound as a white crystalline product, m.p. 110
- 113.5C, yield 77.6 %.
H-NMR (CDCQ3) ~: 2.50 (t, 4H, J=6 Hz),
2.65 (s, 3H), 3.53 (s, 2H),
4.10 (br, 4H), 4.54 (br, 2H),
6.5 - 7.2 (m, 4H)
IR (KBr) cm 1 3450, 3300, 2800, 1605, 1405, 1280,
1260, 1240, 1225, 1145, 990, 925, 740
Example 49
15i) Methyl 4-(2,5-diacetoxy-3,4-dimethoxy-6-methyl-
benzyl)-1-piperazinecarbodithioate (Com. No. 48)
In a nitrogen atmosphere, 0.50 g (1.34 mmol.) of
methyl 4-(2,5-dihydroxy-3,4-dimethoxy-6-methylbenzyl)-1-
piperazinecarbodithioate was dissolved in 5 ml of dichl-
20 oromethane. To the resulting solution was added 0.30 g(2.96 mmol.) of triethylamine. The solution was then
chilled with ice, and to the chilled solution was drop-
wise added a solution of 0.25 g (2.96 mmol.) of 95 %-
acetyl chloride in 3 ml of dichloromethane. The mixture
25 was then stirred for 6 hours. To the mixture were then
added 10 ml of dichloromethane and a small amount of a
saturated aqueous sodium hydrogen carbonate solution.
The mixture was well shaken, and the organic solvent
poriton was taken out. The organic portion was dried
30 over anhydrous sodium sulfate and placed under reduced
pressure to give 0.63 g of methyl 4-(2,5-diacetoxy-3,4-
dimethoxy-6-methylbenzyl)-1-piperazinecarbodithioate as
an oil.
.
1 337768
ii) Methyl 4-(2,5-diacetoxy-3,4-dimethoxy-6-methyl-
benzyl)-1-piperazinecarbodithioate hydrochloride
In 10 ml of dichloromethane was dissolved 0.63 g
(1.38 mmol.) of the above oil. The solution was chilled
5 with ice, and to the chilled solution was introduced
gaseous hydrogen chloride. The solvent was distilled off
under reduced pressure. The obtained residue was cry-
stallized from a mixture of 4 ml of ether, a small amount
of acetone and 2 ml of dichloromethane. The precipitated
10 crystals were collected by filtration to give 0.54 g of
the desired compound as a white powder, m.p. 194 - 195C
(decomp.), yield 79.7 Y0.
H-Nr~R (CDCl3)~ : 2.34 (s, 3H), 2.35 (s, 3H), 2.43
(s, 3H), 2.66 (s, 3H), 2.8 - 3.6
(m, 4H), 3.84 (s, 3H), 3.8 - 5.3
(m, 4H), 3.88 (s, 3H), 4.20 (s,2H)
IR (KBr) cm 1 3000, 2950, 2500, 2420, 1750, 1605,
1475, 1450, 1410, 1370, 1350, 1270,
1250, 1200, 1170, 1105, 1060, 1010,
950, 940, 910, 880
Example 50
Methyl 4-(2,3,4-trimethoxybenzoyl)-1-piperazine-
carbodithioate (Com. No. 56)
In a nitrogen atmosphere, 10 ml (138 mmol.) of thio-
25 nyl chloride was added to 1.00 g (4.71 mmol.) of 2,3,4-
trimethoxybenzoic acid. The mixture was refluxed under
heating for 2 hours. The solvent was distilled off under
reduced PLeS~ULe. To the residue was added 10 ml of dry hPnzPn~ and the
mixture was placed under reduced pressure to distill off
30 benzene. This procedure was repeated once. To the resi-
due was dropwise added at room temperature a solution of
0.88 g (4.74 mmol., purity 95 %) of methyl 1-piperazine-
carbodithioate in 12 ml of dichloromethane. In the
~ 3377 68
_ 76 -
course of the addition, 0.48 g (4.74 mmol.) of triethyl-
amine was added to the mixture. The resulting mixture
was then stirred overnight. The reaction mixture was
washed successively with 1-N hydrochloric acid and a
5 saturated aqueous sodium chloride solution, dried over
anhydrous sodium sulfate, and placed under pressure to
distill off the solvent. The residue was crystallized
from acetone. The crystals were collected by filtration.
The filtrate was concentrated, and additional crystals
10 were further precipitated from the concentrated filtrate
by addition of a small amount of ethanol. These crystal-
line portions were combined to give 0.90 g of the desired
compound as a white crystalline product, m.p. 149 - 150 C
(decomp.), yield 51.6 %.
1H-r~MR (CDCQ3)~ : 2.67 (5, 3H), 3.2 - 3.6 (m, 2H),
3.6 - 3.9 (m, 2H), 3.88 (s, 9H),
3.9 - 4.4 (m, 4H),
6.70 (d, lH, J=8.6 Hz),
6.98 (d, lH, J=8.6 Hz)
IR (KBr) cm : 2930, 2830, 1620, 1595, 1495, 1475,
1450, 1425, 1365, 1280, 1235, 1215,
1180, 1155, 1095, 1040, 1000, 925,
900, 820, 810, 750, 700
Example 51
i) Methyl 4-(2-chlorobenzyl)-1-piperazine-
carbodithioate (Com. No. 2)
In 16 ml of ethanol, 1.61 g (10 mmol.) of 2-chloro-
benzyl chloride, 1.76 g (10 mmol.) of methyl 1-piper-
- azinecarbondithioate and 1.06 g (10 mmol.) of sodium car-
30 bonate were heated to reflux for 4 hours. Ethanol was
distilled off under reduced pressure, and to the residue
was added water. The a~.ueous mixture was extracted with
30 ml of ether. The ether e~tract was shaken with 15 ml
_ ~ 77 ~ l 337768
of 3N-hydrochloric acid. There were separated three
layers. The aqueous portion and the oil portion were
taken out and combined. The combined mixture was made
alkaline with 1-N aqueous sodium hydroxide solution and
5 extracted with ether. The ether portion was washed with
a saturated aqueous sodium chloride solution, dried over
anhydrous sodium sulfate, and placed under reduced pres-
sure to distill off the solvent. The residue was puri-
fied over a silica gel column to give 1.03 g of methyl
10 4-(2-chlorobenzyl)-1-piperazinecarbothioate as a pale
brown oil, yield 34.3 %.
H-NMR (CDCQ3) ~: 2.5 - 2.8 (m, 4H), 2.66 (s, 3H),
3.64 (s, 2H), 3.9 - 4.3 (m, 4H),
7.1 - 7.5 (m, 4H),
ii) Methyl 4-(2-chlorobenzyl)-1-piperazine-
carbodithioate hydrochloride
In 20 ml of ethyl acetate was dissolved 0.98 g of
the above-obtained product. To the solution was added
1.5 ml of 6-N hydrochloric acid in ethanol, and the mix-
20 ture was stirred. Precipiated crystals were collected byfiltration and washed with ethyl acetate to give 900 mg
of the desired compound as a pale yellow crystalline
product, m.p. 235C (decomp.)
1H-NMR (CDC~3/CD30D = 6/1) ~:
2.63 (s, 3H), 2.8 - 4.2 (m, 6H),
4.47 (s, 2H:), 4.9 - 5.5 (m, 2H),
7.2 - 8.1 (m, 4H),
IR (KBr) cm : 2700 -2100, 1465, 1410, 1265, 1245,
1215, 1195, 1110, 955, 745
- 78 - l 3 3 7 7 6 ~
Example 52
i) Methyl 4-(4-methoxybenzyl)-1-piperazine-
carbodithioate (Com. No. 7)
In a nitrogen atmosphere, 2.00 g (14.5 mmol.) of 4-
5 methoxybenzyl alcohol was dissolved in 10 ml of dichloro-
methane. Under chilling with ice, to the solution was
dropwise added a solution of 1.05 ml (14.5 mmol.) of
thionyl chloride in 2 ml of dichloromethane. The mixture
was then stirred at room temperature for 1 hour. The
10 solvent was distilled off under reduced pressure. The
residue was mixed with 2.90 g (14.5 mmol., purity 88.1%)
of m2thyl 1-pipera~inecarbodithioate, 1.54 g (14.5 mmol.)
of anhydrous sodium carbonate and 25 ml of ethanol. The
mixtru~ was refluxed under heating for 14.5 hours. The
lS solvent was distilled off under reduced pressure. The
residue was mixed with 10 ml of dichloromethane and 10 ml
of water. The mixture was allowed to give separated
layers, and filtered to remove insolubles. The organic
solvent portion was washed WL th water and a saturated
20 aqueous sodium chloride solution, dried over anhydrous
sodium sulfate, and placed under reduced pressure to
distill off the solvent. The residue was purified over a
silica gel column to give 1.46 g of methyl 4-(4-methoxy-
benzyl)-1-piperazinecarbodithioate as a pale yellow oil,
25 yield 33.9 %.
ii) Methyl 4-(4-methoxybenzyl)-1-piperazine-
carbodithioate hydrochloride
In 5.8 ml of dichloromethane was dissolved 1.46 g
(2.92 mmol.) of the above-obtained oil. Under chilling
30 with ice, to the solution was dropwise added 4.92 ml of
1-N HCl/ether solution, and the mixture was
stirred. Precipiated crystals were collected by filtra-
tion and washed with 5 ml of ether to give 1.43 g of the
~ - 79 -
1 337768
desired compound as a white crystalline powder, m.p. 205
- 206C (decomp.), yield 87.4 %.
H-NMR (CD30D)~ : 2.65 (s, 3H), 3.0 - 4.0 (m, 6H),
3.83 (s, 3H), 4.34 (s, 2H),
4.9 - 5.6 (m, 2H),
7.02 (d, 2H, J=8.8 Hz),
7.49 (d, 2H, J=8.8 Hz)
IR (KBr) cm 1 2900, 2830, 2650, 2520, 2450, 1610,
1580, 1510, 1460, 1405, 1300, 1270,
- 1250, 1210, 1175, 1120, 1105, 1025,
945, 845, 820
Example 53
i) Methyl 4-(3-methoxybenzyl)-1-piperazine-
carbodithioate (Com. No. 6)
In a nitrogen atmosphere, 1.57 g (10.0 mmol.) of 3-
methoxybenzyl chloride, 2.00 g (10.0 mmol., purity 88.1
~) of methyl 1-piperazinecarbodithioate, 1.06 g (10.0
mmol.) of anhydrous sodium carbonate and 20 ml of
ethanol. The mixtrue was refluxed under heating for 5
20 hours. The solvent was distilled off under reduced
pressure. The residue was mixed with 15 ml of dichloro-
methane and 10 ml of water. The mixture was allowed to
give separated layers. The organic solvent portion was
washed with water and a saturated aqueous sodium chloride
25 solution, dried over anhydrous sodium sulfate, and placed
under reduced pressure to distill off the solvent. The
residue was purified over a silica gel column to give
2.46 g of methyl 4-(3-methoxybenzyl)-1-piperazinecarbo-
dithioate as a colorless crystalline product, yield 82.8
30 %.
ii) Methyl 4-(3-methoxybenzyl)-1-piperazine-
carbodithioate hydrochloride
- 80 -
1 337768
In 20 ml of ethyl acetate was dissolved 2.31 g (7.79
mmol.) of the above-obtained product. ~nder chilling
with ice, to the solution was dropwise added 2.0 ml of
6-N hydrochloric acid in ethanol, and the mixture was
5 stirred. Precipiated crystals were collected by filtra-
tion and washed with 10 ml of ethyl acetate to give 1.63
g of the desired compound as a white crystalline powder,
m.p. 183 - 184C (decomp.), yield 62.9 %.
1H-NMR (CD30D) ~: 2.65 (s, 3H), 2.6 - 3.7 (m, 4H),
3.86 (s, 3H), 3.9 - 4.4 (m, 4H),
4.9 - 5.5 (m, 2H),
6.8 - 7.5 (m, 4H)
IR (KBr) cm : 3050, 2990, 2910, 2830, 2660, 2500,
2420, 1600, 1580, 1490, 1460, 1410,
1370, 1340, 1295, 1260, 1250, 1200,
1190, 1170, 1120, 1070, 1030, 1000,
950, 860, 795, 775, 740, 690
Example 54
i) Methyl 4-(2-methylbenzyl)-1-piperazine-
carbodithioate (Com. No. 3)
1.405 g (10 mmol.) of 2-methylbenzyl chloride, 1.76
g (10 mmol.) of methyl 1-piperazinecarbodithioate, 1.06 g
(10 mmol.) of anhydrous sodium carbonate and 14 ml of
ethanol. The mixtrue was refluxed under heating for 2.5
25 hours. Ethanol was distilled off under reduced pressure.
The residue was mixed with water and ether. The organic
solvent portion was taken out, and to the portion was
added 15 ml of 3-N hydrochloric acid. The aqueous por-
tion was neutralized with 1-N aqueous sodium hydroxide
30 solution, and extracted with ethyl acetate. The ethyl
acetate portion was washed with water and a saturated
aqueous sodium chloride solution, dried over anhydrous
sodium sulfate, and placed under reduced pressure to
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distill off the solvent. The residue was purified over a
silica gel column to give 790 mg of methyl 4-(2-methyl-
benzyl)-1-piperazinecarbodithioate as a white crystalline
product, yield 28.2 h.
1H-NMR (CDC~3) : 2.36 (s, 3H), 2.51 (t, 4H, J=5Hz),
2.64 (s, 3H), 3.48 (s, 2H), 3.8 -
4.4 (m, 4H), 7.0 - 7.4 (m, 4H)
ii) Methyl 4-(2-methylbenzyl)-1-piperazine-
carbodithioate hydrochloride
In 7 ml of ethyl acetate was dissolved 670 mg (2.39
mmol.) of the above-obtained product. To the solution
was added 1.0 ml of 6-N HCl in ethanol, and
the mixture was stirred. Precipiated crystals were col-
lected by filtration and washed with of ethyl acetate to
15 ~ive 610 m~ of the desired compound as a colorless cry-
stalline product, m.p. 214C (decomp.), yield 80.6 %.
H-NMR (CD30D/CDC~3=3/1)
2.49 (s, 3H), 2.67 (s, 3H), 2.8 -
4.2 (m, 6H), 4.38 (s, 2H),
4.9 - 5.4 (m, 2H),
7.1 - 7.8 (m, 4H)
IR (KBr) cm : 2700 - 2200, 1470, 1430, 1400, 1270,
1210, 1020, 955, 755
Preparation Example 1 (Powder)
25 Piperazine derivative of the invention 10 wt. parts
~leavy magnesium oxide 10 wt. parts
L~ctose 80 wt. parts
The above compounds were mixed homogeneously and
pulverized to prepare a powder.
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Preparation Example 2 (Powder)
Piperazine derivative of the invention 10 wt. parts
Synthetic aluminum silicate10 wt. parts
Calcium hydrogenphospate 5 wt. parts
5 Lactose 75 wt. parts
The above compounds were mixed homogeneously and
pul~erized to prepare a powder.
Preparation Example 3 (Granules)
Piperazine derivative of the invention 50 wt. parts
10 Starch 10 wt. parts
L"~cto.se 15 wt. parts
Crystalline cellulose 20 wt. parts
Polyvinyl alcohol 5 wt. parts
~ater 30 wt. parts
' The ab~ve cc.mpounds were mixed and kneaded homogene-
ously, dried, pulverized and sieved to prepare granules.
Preparation Example 4 (Pellets)
99 parts by weight of the granules of Preparation
Example 3 were mixed with one part of calcium stearate,
20 and the mixture was pelletized under pressure to give
a pellet of diameter of 10 mm.
Preparation Example 5 (Injection Solution)
Piperazine derivative of the invention 0.5 wt. part
Nonionic surface active agent 2.5 wt. parts
25 Fhysiolo~ical saline solution97 wt. parts
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The above compounds were mixed and sanitized to
prepare the injection solution.
Preparation Example 6 (Capsuls)
The powder of Preparation Example 1 is charged in a
5 commercially available capsule case to give capsules.
